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Alharbi A, Albasyouni S, Al-Shaebi E, Al Quraishy S, Abdel-Gaber R. Neuroprotective and antimalarial effects of Juglans regia leaf extracts in a murine model of cerebral malaria. Front Vet Sci 2025; 12:1537686. [PMID: 40260212 PMCID: PMC12009927 DOI: 10.3389/fvets.2025.1537686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2024] [Accepted: 03/24/2025] [Indexed: 04/23/2025] Open
Abstract
Background Malaria is a major public health problem caused by the apicomplexan Plasmodium parasite. Cerebral malaria (CM) is the most critical outcome of Plasmodium infection. It is becoming more difficult to manage, particularly in areas of multi-drug resistance. Scientists are focused on identifying alternative strategies to combat malaria infection. Therefore, this study was designed to evaluate the activity of Juglans regia leaf extract (JRLE) in Plasmodium berghei-infected C57BL/6 mice. Methods The J. regia leaf extract (JRLE) was prepared using methanol and characterized by Fourier-transform infrared spectroscopy (FT-IR). Female C57BL/6 mice were divided into six groups (5 mice/group): control, non-infected but JRLE-treated (500 mg/kg), P. berghei-infected non-treated, and P. berghei-infected treated with JRLE (250 or 500 mg/kg) or chloroquine (10 mg/kg). Groups (3-6) were infected intraperitoneally with P. berghei (1 × 10⁵). Treatment (oral JRLE or chloroquine) was administered for 5 days starting on day 4. Parasitemia, survival, and body weight were assessed, and brains were collected on day 9 p.i. for histopathological analysis (H&E staining) and GFAP immunohistochemistry. GABA, glutamate, neurotransmitters (epinephrine, norepinephrine, dopamine, serotonin), and mRNA expression of signaling genes (Chrnb2, Gabbr1, Gnai1, Gria2) were evaluated using ELISA and real-time PCR. Results Phytochemical screening by FT-IR demonstrated the presence of 10 functional groups in the JRLE. By day 9 after infection with the P. berghei parasite, the parasitemia was significantly reduced after JRLE treatment with a dose of 500 mg/kg (6.33% ± 1.18%) compared to the infected group (23.84% ± 2.06%) with a positive correlation with body weight. Our data showed that JRLE prolonged the survival curve of the infected mice. JRLE ameliorates the reduction of the brain index caused by P. berghei infection. Furthermore, histological analysis showed that infection with P. berghei exacerbates brain damage as evidenced by degeneration of Purkinje cells, cerebral hemorrhage, intravascular sequestrations of parasitized red blood corpuscles (pRBCs), and infiltration of lymphocytes. At the same time, treatment with JRLE mitigates the brain injury induced by the infection. JRLE reduced the level of GFAP expression in the brain tissue of the infected mice. Additionally, treatment with JRLE ameliorates the brain neurotransmitter disbalance (i.e., epinephrine, norepinephrine, dopamine, and serotonin) after Plasmodium infection. Upon JRLE treatment, Chrnb2, Gnai1, and Gabbr1 mRNA expression were down-regulated in the brain tissues derived from infected female C57BL/6 mice. Meanwhile, mRNA expression of Gria2 was up-regulated after JRLE inoculation. Our study proved that JRLE significantly ameliorated the neurotransmitter markers by increasing GABA levels and decreasing the glutamate level in the brain of P. berghei-infected mice. Conclusion Taken together, the data reported here illustrate that J. regia leaf extracts possess potent antimalarial effects and may offer a potential drug lead for developing a safe, effective, and affordable antimalarial therapy. Further studies are recommended to include the broader organ-specific effects of plant extract.
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Affiliation(s)
| | | | | | | | - Rewaida Abdel-Gaber
- Department of Zoology, College of Science, King Saud University, Riyadh, Saudi Arabia
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Zhang Q, Zhu L, Li H, Chen Q, Li N, Li J, Zhao Z, Xiao D, Tang T, Bi C, Zhang Y, Zhang H, Zhang G, Li M, Zhu Y, Zhang J, Kong J. Insights and progress on the biosynthesis, metabolism, and physiological functions of gamma-aminobutyric acid (GABA): a review. PeerJ 2024; 12:e18712. [PMID: 39703920 PMCID: PMC11657192 DOI: 10.7717/peerj.18712] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Accepted: 11/24/2024] [Indexed: 12/21/2024] Open
Abstract
GABA (γ-aminobutyric acid) is a non-protein amino acid that occurs naturally in the human brain, animals, plants and microorganisms. It is primarily produced by the irreversible action of glutamic acid decarboxylase (GAD) on the α-decarboxylation of L-glutamic acid. As a major neurotransmitter in the brain, GABA plays a crucial role in behavior, cognition, and the body's stress response. GABA is mainly synthesized through the GABA shunt and the polyamine degradation pathways. It works through three receptors (GABAA, GABAB, and GABAC), each exhibiting different pharmacological and physiological characteristics. GABA has a variety of physiological roles and applications. In plants, it regulates growth, development and stress responses. In mammals, it influences physiological functions such as nervous system regulation, blood pressure equilibrium, liver and kidneys enhancement, hormone secretion regulation, immunity enhancement, cancer prevention, as well as anti-aging effects. As a biologically active ingredient, GABA possesses unique physiological effects and medicinal value, leading to its widespread application and substantially increased market demand in the food and pharmaceutical industries. GABA is primarily produced through chemical synthesis, plant enrichment and microbial fermentation. In this review, we first make an overview of GABA, focusing on its synthesis, metabolism, GABA receptors and physiological functions. Next, we describe the industrial production methods of GABA. Finally, we discuss the development of ligands for the GABA receptor binding site, the prospects of GABA production and application, as well as its clinical trials in potential drugs or compounds targeting GABA for the treatment of epilepsy. The purpose of this review is to attract researchers from various fields to focus on GABA research, promote multidisciplinary communications and collaborations, break down disciplinary barriers, stimulate innovative research ideas and methods, and advance the development and application of GABA in medicine, agriculture, food and other fields.
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Affiliation(s)
- Qingli Zhang
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Lei Zhu
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Hailong Li
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Qu Chen
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Nan Li
- Department of Rehabilitation, Qingdao Binhai College Affiliated Hospital, Qingdao, China
| | - Jiansheng Li
- Department of Nephrology, Gansu Provincial Hospital of Traditional Chinese Medicine, Lanzhou, Gansu, China
| | - Zichu Zhao
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Di Xiao
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Tingting Tang
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Chunhua Bi
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Yan Zhang
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Haili Zhang
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Guizhen Zhang
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Mingyang Li
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Yanli Zhu
- College of Life Sciences and Engineering, Northwest Minzu University, Lanzhou, China
| | - Jingjing Zhang
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
| | - Jingjing Kong
- Department of Medicine, Qingdao Binhai University, Qingdao, Shandong, China
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Gonda X, Tarazi FI, Dome P. The emergence of antidepressant drugs targeting GABA A receptors: A concise review. Biochem Pharmacol 2024; 228:116481. [PMID: 39147329 DOI: 10.1016/j.bcp.2024.116481] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2024] [Revised: 08/06/2024] [Accepted: 08/09/2024] [Indexed: 08/17/2024]
Abstract
Depression is among the most common psychiatric illnesses, which imposes a major socioeconomic burden on patients, caregivers, and the public health system. Treatment with classical antidepressants (e.g. tricyclic antidepressants and selective serotonine reuptake inhibitors), which primarily affect monoaminergic systems has several limitations, such as delayed onset of action and moderate efficacy in a relatively large proportion of depressed patients. Furthermore, depression is highly heterogeneus, and its different subtypes, including post-partum depression, involve distinct neurobiology, warranting a differential approach to pharmacotherapy. Given these shortcomings, the need for novel antidepressants that are superior in efficacy and faster in onset of action is fully justified. The development and market introduction of rapid-acting antidepressants has accelerated in recent years. Some of these new antidepressants act through the GABAergic system. In this review, we discuss the discovery, efficacy, and limitations of treatment with classic antidepressants. We provide a detailed discussion of GABAergic neurotransmission, with a special focus on GABAA receptors, and possible explanations for the mood-enhancing effects of GABAergic medications (in particular neurosteroids acting at GABAA receptors), and, ultimately, we present the most promising molecules belonging to this family which are currently used in clinical practice or are in late phases of clinical development.
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Affiliation(s)
- Xenia Gonda
- Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary; NAP3.0-SE Neuropsychopharmacology Research Group, Hungarian Brain Research Program, Semmelweis University, Budapest, Hungary.
| | - Frank I Tarazi
- Department of Psychiatry and Neurology, Harvard Medical School and McLean Hospital, Boston, MA, USA
| | - Peter Dome
- Department of Psychiatry and Psychotherapy, Semmelweis University, Budapest, Hungary; Nyiro Gyula National Institute of Psychiatry and Addictology, Budapest, Hungary
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Franchini L, Orlandi C. Deorphanization of G Protein Coupled Receptors: A Historical Perspective. Mol Pharmacol 2024; 105:374-385. [PMID: 38622017 DOI: 10.1124/molpharm.124.000900] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 03/26/2024] [Accepted: 04/01/2024] [Indexed: 04/17/2024] Open
Abstract
Counting over 800 members, G protein coupled receptors (GPCRs) form the largest family of membrane receptors encoded in the human genome. Since the discovery of G proteins and GPCRs in the late 1970s and early 1980s, a significant portion of the GPCR research has been focused on identifying ligand/receptor pairs in parallel to studies related to their signaling properties. Despite significant advancements, about a fourth of the ∼400 nonodorant GPCRs are still considered orphan because their natural or endogenous ligands have yet to be identified. We should consider that every GPCR was once an orphan and that endogenous ligands have often been associated with biologic effects without a complete understanding of the molecular identity of their target receptors. Within this framework, this review offers a historical perspective on deorphanization processes for representative GPCRs, including the ghrelin receptor, γ aminobutyric acid B receptor, apelin receptor, cannabinoid receptors, and GPR15. It explores three main scenarios encountered in deorphanization efforts and discusses key questions and methodologies employed in elucidating ligand-receptor interactions, providing insights for future research endeavors. SIGNIFICANCE STATEMENT: Understanding how scientists have historically approached the issue of GPCR deorphanization and pairing of biologically active ligands with their cognate receptors are relevant topics in pharmacology. In fact, the biology of each GPCR, including its pathophysiological involvement, has often been uncovered only after its deorphanization, illuminating druggable targets for various diseases. Furthermore, uncovered endogenous ligands have therapeutic value as many ligands-or derivates thereof-are developed into drugs.
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Affiliation(s)
- Luca Franchini
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York
| | - Cesare Orlandi
- Department of Pharmacology and Physiology, University of Rochester Medical Center, Rochester, New York
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5
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Zhao H, Li X, Zhang M. Nickel-catalyzed mild synthesis of functional γ-amino butyric acid esters via direct α-C(sp 3)-H allylation of N-alkyl anilines with allyl sulfones. Org Biomol Chem 2023; 21:8883-8887. [PMID: 37902574 DOI: 10.1039/d3ob01494k] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/31/2023]
Abstract
Herein, by employing a readily available Ni(OAc)2·4H2O/TBHP catalyst system, we present a new method for mild synthesis of α-methylene-γ-amino butyric acid esters via direct α-C(sp3)-H allylation of N-alkyl anilines with allyl sulfones under oxidative nickel catalysis. The synthetic protocol proceeds with good substrate and functional group compatibility, operational simplicity, the use of base metal catalysts and easily accessible feedstocks, and no need for pre-functionalization of the α-site of N-alkyl anilines. In addition, the obtained products are applicable for further elaboration of functional molecules.
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Affiliation(s)
- He Zhao
- School of Chemistry and Chemical Engineering, South China University of Technology, Wushan Rd-381, Guangzhou 510641, People's Republic of China.
- Chemistry & Chemical Engineering, Yancheng Institute of Technology, Yancheng, China
| | - Xiu Li
- School of Chemistry and Chemical Engineering, South China University of Technology, Wushan Rd-381, Guangzhou 510641, People's Republic of China.
| | - Min Zhang
- School of Chemistry and Chemical Engineering, South China University of Technology, Wushan Rd-381, Guangzhou 510641, People's Republic of China.
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Wang Q, Wu S, Zou J, Liang X, Mou C, Zheng P, Chi YR. NHC-catalyzed enantioselective access to β-cyano carboxylic esters via in situ substrate alternation and release. Nat Commun 2023; 14:4878. [PMID: 37573355 PMCID: PMC10423276 DOI: 10.1038/s41467-023-40645-8] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Accepted: 08/04/2023] [Indexed: 08/14/2023] Open
Abstract
A carbene-catalyzed asymmetric access to chiral β-cyano carboxylic esters is disclosed. The reaction proceeds between β,β-disubstituted enals and aromatic thiols involving enantioselective protonation of enal β-carbon. Two main factors contribute to the success of this reaction. One involves in situ ultrafast addition of the aromatic thiol substrates to the carbon-carbon double bond of the enal substrate. This reaction converts almost all enal substrate to a Thiol-click Intermediate, significantly reducing aromatic thiol substrates concentration and suppressing the homo-coupling reaction of enals. Another factor is an in situ release of enal substrate from the Thiol-click Intermediate for the desired reaction to proceed effectively. The optically enriched β-cyano carboxylic esters from our method can be readily transformed to medicines that include γ-aminobutyric acids derivatives such as Rolipram. In addition to synthetic utilities, our control of reaction outcomes via in situ substrate modulation and release can likely inspire future reaction development.
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Affiliation(s)
- Qingyun Wang
- National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, 550025, China
| | - Shuquan Wu
- Center for Industrial Catalysis and Cleaning Process Development, School of Chemical Engineering, Guizhou Minzu University, Guiyang, 550025, China
| | - Juan Zou
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China
| | - Xuyang Liang
- National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, 550025, China
| | - Chengli Mou
- School of Pharmacy, Guizhou University of Traditional Chinese Medicine, Guiyang, 550025, China
| | - Pengcheng Zheng
- National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, 550025, China.
| | - Yonggui Robin Chi
- National Key Laboratory of Green Pesticide, Key Laboratory of Green Pesticide and Agricultural Bioengineering, Ministry of Education, Guizhou University, Guiyang, 550025, China.
- School of Chemistry, Chemical Engineering, and Biotechnology, Nanyang Technological University, Singapore, 637371, Singapore.
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7
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Chen L, Qu Q, Ran CK, Wang W, Zhang W, He Y, Liao LL, Ye JH, Yu DG. Photocatalytic Carboxylation of C-N Bonds in Cyclic Amines with CO 2 by Consecutive Visible-Light-Induced Electron Transfer. Angew Chem Int Ed Engl 2023; 62:e202217918. [PMID: 36680762 DOI: 10.1002/anie.202217918] [Citation(s) in RCA: 20] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Revised: 01/18/2023] [Accepted: 01/19/2023] [Indexed: 01/22/2023]
Abstract
Visible-light photocatalytic carboxylation with CO2 is highly important. However, it still remains challenging for reluctant substrates with low reduction potentials. Herein, we report a novel photocatalytic carboxylation of C-N bonds in cyclic amines with CO2 via consecutive photo-induced electron transfer (ConPET). It is also the first photocatalytic reductive ring-opening reaction of azetidines, pyrrolidines and piperidines. This strategy is practical to transform a variety of easily available cyclic amines to valuable β-, γ-, δ- and ϵ-amino acids in moderate-to-excellent yields. Moreover, the method also features mild and transition-metal-free conditions, high selectivity, good functional-group tolerance, facile scalability and product derivations. Mechanistic studies indicate that the ConPET might be the key to generating highly reactive photocatalysts, which enable the reductive activation of cyclic amines to generate carbon radicals and carbanions as the key intermediates.
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Affiliation(s)
- Lin Chen
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
| | - Quan Qu
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
| | - Chuan-Kun Ran
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
| | - Wei Wang
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
| | - Wei Zhang
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
| | - Yi He
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
| | - Li-Li Liao
- School of Chemistry and Chemical Engineering, Chongqing University, Chongqing, 400030, P. R. China
| | - Jian-Heng Ye
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China
| | - Da-Gang Yu
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China.,State Key Laboratory of Elemento-Organic Chemistry, Nankai University, Tianjin, 300071, P. R. China
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Li Q, Zhang X, Zeng T, Yang B, Duan J, Tang Y. Clinical characteristics and prognosis of anti-GABABR encephalitis: A single-center experience. Medicine (Baltimore) 2023; 102:e32956. [PMID: 36800611 PMCID: PMC9936044 DOI: 10.1097/md.0000000000032956] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/19/2023] Open
Abstract
The purpose of this study was to assess the demographic data, clinical manifestations, cerebrospinal fluid (CSF), hematology, brain magnetic resonance imaging, electroencephalograms, and therapy and prognosis related to anti-gamma-aminobutyric acid B (anti-GABABR) encephalitis. We retrospectively examined the demographic data, clinical manifestations, laboratory results, brain magnetic resonance imaging, electroencephalograms, and therapy and prognosis of 6 patients with anti-GABABR encephalitis. We used the clinical data of patients with anti-GABABR encephalitis admitted to the Department of Neurology of Mianyang Central Hospital obtained from January 2017 to September 2020. Six patients with anti-GABABR encephalitis were included. Generalized tonic-clonic seizure was the first clinical symptom in 5 patients, while 1 patient first showed behavior disorder. After the first clinical symptom attack, 2 patients developed a memory deficit, 4 cases showed cognitive decline, 3 cases showed behavior disorder, 1 patient developed status epilepticus and only 1 patient returned to normal. CSF testing indicated normal intracranial pressure in 5 patients and elevated pressure in only 1 patient. Additionally, the cerebrospinal fluid tests revealed slight leukocytosis in all patients and elevated protein levels in 5 patients. The anti-GABABR antibody was positive in both serum and CSF in all patients. Brain magnetic resonance imaging showed limbic system lesions in 4 patients. Long-term electroencephalograms revealed abnormal waves in half of the patients. All patients were treated with high dosages of methylprednisolone, which was combined with intravenous immunoglobulin in 2 patients; symptoms were improved in 4 patients, 1 patient showed no significant change and 1 patient with status epilepticus died of severe pneumonia during hospitalization. Epilepsy is the most common initial symptom in patients of anti-GABABR encephalitis. Many patients are also affected by tumors. Early immunotherapy can achieve excellent effects, the long-term prognosis is good for most patients.
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Affiliation(s)
- Qiang Li
- Department of Neurology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Xianwen Zhang
- Department of Neurology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Ting Zeng
- Department of Neurology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Bufan Yang
- Department of Neurology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Jingfeng Duan
- Department of Neurology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
| | - Yufeng Tang
- Department of Neurology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China
- * Correspondence: Yufeng Tang, Department of Neurology, Mianyang Central Hospital, School of Medicine, University of Electronic Science and Technology of China, Mianyang, China (e-mail: )
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Okuda DT, Kantor D, Jaros M, deVries T, Hunter S. Arbaclofen extended-release tablets for spasticity in multiple sclerosis: randomized, controlled clinical trial. Brain Commun 2022; 4:fcac300. [PMID: 36519155 PMCID: PMC9732858 DOI: 10.1093/braincomms/fcac300] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2022] [Revised: 08/27/2022] [Accepted: 11/21/2022] [Indexed: 09/10/2024] Open
Abstract
Baclofen, a racemic GABA-B (GABAB) receptor agonist, is commonly used for the management of multiple sclerosis-related spasticity but is associated with frequent dosing and poor tolerability. Arbaclofen, the active R-enantiomer of baclofen, exhibits 100- to 1000-fold greater specificity for the GABAB receptor compared with the S-enantiomer and ∼5-fold greater potency compared with racemic baclofen. Arbaclofen extended-release tablets have a dosing interval of 12 hours and have shown a favourable safety and efficacy profile in early-phase clinical development. The current Phase 3 study was designed to evaluate the efficacy and safety of arbaclofen extended-release tablets in patients with multiple sclerosis-related spasticity. In this multicentre, double-blind, placebo-controlled study, adults with multiple sclerosis-related spasticity were randomized to arbaclofen extended-release 40 mg/day, arbaclofen extended-release 80 mg/day or placebo for 12 weeks. The co-primary end-points were the change from baseline to Week 12 in the Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score and the Clinical Global Impression of Change score. A hierarchical testing procedure was used to evaluate the co-primary end-points; analyses for the 80 mg/day group were considered inferential only if the arbaclofen extended-release 40 mg/day and placebo groups demonstrated a statistically significant difference (P ≤ 0.05) for both end-points. Five hundred thirty-six patients were included in the study. At Week 12, the least squares mean change from baseline in Total Numeric-transformed Modified Ashworth Scale in the Most Affected Limb score was -1.67 (95% confidence interval: -1.97 to -1.36) and -1.28 (95% confidence interval: -1.57 to -0.99) in the arbaclofen extended-release 40 mg/day and placebo groups, respectively (least squares mean difference: -0.39; P < 0.048). Improvements were seen in the mean Clinical Global Impression of Change scores for both the arbaclofen extended-release 40 mg/day and placebo groups; however, no statistically significant difference was observed between them (least squares mean difference: -0.10; P = 0.43). Most adverse events were of mild-moderate severity. Arbaclofen extended-release 40 mg/day for 12 weeks significantly reduced multiple sclerosis-related spasticity compared with placebo and was safe and well tolerated over the 12-week treatment period. Although arbaclofen extended-release 40 mg/day improved Clinical Global Impression of Change scores, a significant difference from placebo was not observed.
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Affiliation(s)
- Darin T Okuda
- Neurology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8806, USA
| | - Daniel Kantor
- Neurology, Florida Atlantic University, Boca Raton, FL 33431, USA
- Clinical Immunology, Nova Southeastern University, Fort Lauderdale, FL 33314, USA
| | - Mark Jaros
- Summit Analytical, Denver, CO 80238, USA
| | - Tina deVries
- Research and Development, RVL Pharmaceuticals, Inc., Bridgewater, NJ 08807, USA
| | - Samuel Hunter
- Advanced Neurosciences Institute, Franklin, TN 37064, USA
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10
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Unravelling biological roles and mechanisms of GABA BR on addiction and depression through mood and memory disorders. Biomed Pharmacother 2022; 155:113700. [PMID: 36152411 DOI: 10.1016/j.biopha.2022.113700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 09/08/2022] [Accepted: 09/13/2022] [Indexed: 11/23/2022] Open
Abstract
The metabotropic γ-aminobutyric acid type B receptor (GABABR) remains a hotspot in the recent research area. Being an idiosyncratic G-protein coupled receptor family member, the GABABR manifests adaptively tailored functionality under multifarious modulations by a constellation of agents, pointing to cross-talk between receptors and effectors that converge on the domains of mood and memory. This review systematically summarizes the latest achievements in signal transduction mechanisms of the GABABR-effector-regulator complex and probes how the up-and down-regulation of membrane-delimited GABABRs are associated with manifold intrinsic and extrinsic agents in synaptic strength and plasticity. Neuropsychiatric conditions depression and addiction share the similar pathophysiology of synapse inadaptability underlying negative mood-related processes, memory formations, and impairments. In the attempt to emphasize all convergent discoveries, we hope the insights gained on the GABABR system mechanisms of action are conducive to designing more therapeutic candidates so as to refine the prognosis rate of diseases and minimize side effects.
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Abstract
GABA is the main inhibitory neurotransmitter in the mammalian central nervous system (CNS) and acts via metabotropic GABAB receptors. Neurodegenerative diseases are a major burden and affect an ever increasing number of humans. The actual therapeutic drugs available are partially effective to slow down the progression of the diseases, but there is a clear need to improve pharmacological treatment thus find alternative drug targets and develop newer pharmaco-treatments. This chapter is dedicated to reviewing the latest evidence about GABAB receptors and their inhibitory mechanisms and pathways involved in the neurodegenerative pathologies.
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Affiliation(s)
- Alessandra P Princivalle
- Department of Bioscience and Chemistry, Biomolecular Research Centre, College of Health, Wellbeing and Life Sciences at Sheffield Hallam University, Sheffield, UK.
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12
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Abstract
Gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain, acts at the ionotropic GABAA and GABAC receptors, and the metabotropic GABAB receptor. This chapter summarizes the studies that have investigated the role of the GABAB receptor in stress-related psychiatric disorders including anxiety and mood disorders. Overall, clinical and preclinical evidences strongly suggest that the GABAB receptor is a therapeutic candidate for depression and anxiety disorders. However, the clinical development of GABAB receptor-based drugs to treat these disorders has been hampered by their potential side-effects, particularly those of agonists. Nevertheless, the discovery of novel GABAB receptor allosteric modulators, and increasing understanding of the influence of specific intracellular GABAB receptor-associated proteins on GABAB receptor activity, may now pave the way towards GABAB receptor therapeutics in the treatment of mood and anxiety disorders.
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Affiliation(s)
- Daniela Felice
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland
- APC Microbiome Ireland, University College Cork, Cork, Ireland
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
- APC Microbiome Ireland, University College Cork, Cork, Ireland.
| | - Olivia F O'Leary
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland.
- APC Microbiome Ireland, University College Cork, Cork, Ireland.
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13
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Qi L, Yang PJ, Ji WT, Tao GD, Yang G, Chai Z. Synthesis of chiral β-substituted γ-amino-butyric acid derivatives via enantioconvergent ring opening of racemic 2-(hetero)aryl aziridines with ketene silyl acetals. Org Chem Front 2022. [DOI: 10.1039/d2qo00450j] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Lewis acid-catalyzed enantioconvergent ring opening of racemic 2-(hetero)aryl-N-sulfonyl aziridines with ketene silyl acetals is developed.
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Affiliation(s)
- Ling Qi
- MOE Key Laboratory of Functional Molecular Solids, Anhui Laboratory of Molecule-Based Materials, Institute of Organic Chemistry, College of Chemistry and Materials Science, Anhui Normal University, 189 South Jiuhua Road, Wuhu, Anhui 241002, China
| | - Pei-Jun Yang
- MOE Key Laboratory of Functional Molecular Solids, Anhui Laboratory of Molecule-Based Materials, Institute of Organic Chemistry, College of Chemistry and Materials Science, Anhui Normal University, 189 South Jiuhua Road, Wuhu, Anhui 241002, China
- Anhui Province Key Laboratory of Functional Coordinated Complexes for Materials Chemistry and Application, School of Chemical and Environmental Engineering, Anhui Polytechnic University, Middle Beijing Road, Wuhu, Anhui 241000, China
| | - Wen-Tao Ji
- MOE Key Laboratory of Functional Molecular Solids, Anhui Laboratory of Molecule-Based Materials, Institute of Organic Chemistry, College of Chemistry and Materials Science, Anhui Normal University, 189 South Jiuhua Road, Wuhu, Anhui 241002, China
| | - Gui-De Tao
- MOE Key Laboratory of Functional Molecular Solids, Anhui Laboratory of Molecule-Based Materials, Institute of Organic Chemistry, College of Chemistry and Materials Science, Anhui Normal University, 189 South Jiuhua Road, Wuhu, Anhui 241002, China
| | - Gaosheng Yang
- MOE Key Laboratory of Functional Molecular Solids, Anhui Laboratory of Molecule-Based Materials, Institute of Organic Chemistry, College of Chemistry and Materials Science, Anhui Normal University, 189 South Jiuhua Road, Wuhu, Anhui 241002, China
| | - Zhuo Chai
- MOE Key Laboratory of Functional Molecular Solids, Anhui Laboratory of Molecule-Based Materials, Institute of Organic Chemistry, College of Chemistry and Materials Science, Anhui Normal University, 189 South Jiuhua Road, Wuhu, Anhui 241002, China
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14
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Bareli T, Ahdoot HL, Ben Moshe H, Barnea R, Warhaftig G, Gispan I, Maayan R, Rosca P, Weizman A, Yadid G. Novel Opipramol-Baclofen Combination Alleviates Depression and Craving and Facilitates Recovery From Substance Use Disorder-An Animal Model and a Human Study. Front Behav Neurosci 2021; 15:788708. [PMID: 35002647 PMCID: PMC8733380 DOI: 10.3389/fnbeh.2021.788708] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2021] [Accepted: 11/29/2021] [Indexed: 11/13/2022] Open
Abstract
Substance use disorders (SUDs) are associated with depression and anxiety, with the latter being one of the major factors in substance-seeking and relapse. Due to dose-dependent sedative side effects there is limited efficacy of baclofen treatment for SUDs. Here we suggest the use of a novel combination of opipramol and baclofen (O/B) which is known to attenuate anxiety and depression, for the facilitation of recovery from SUDs. Since both opipramol and baclofen have a common downstream signal transduction, their individual doses could be reduced while still maintaining the benefits of the combination. We tested the O/B combination in both animals and patients. Rats treated with O/B showed significant attenuation in craving behavior and in relapse rate during withdrawal from cocaine. In a double-blind, placebo-controlled pilot study, conducted in a residential detoxification center, 14 males and 3 females, aged 28-60 years were assigned to a study (n = 6) and a placebo (n = 11) group (placebo group: 40 ± 10.5 years; O/B group 40 ± 10.8 years). The participants completed scales measuring depression, anxiety and craving symptoms and provided saliva samples for stress hormone examination [cortisol and dehydroepiandrosterone-sulfate (DHEA-S)]. Participants with polysubstance use disorder (PsUD) treated with O/B showed a reduction in cravings and depression and an increase in DHEA-S and in the DHEA-S/cortisol ratio. Our findings indicate a beneficial effect of O/B treatment. This study suggests a novel candidate for pharmacological treatment of patients with SUD and comorbid mood/anxiety disorders that may facilitate their rehabilitation.
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Affiliation(s)
- Tzofnat Bareli
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Hadas Levi Ahdoot
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Hila Ben Moshe
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Royi Barnea
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Gal Warhaftig
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Iris Gispan
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
| | - Rachel Maayan
- The Laboratory of Molecular Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Paola Rosca
- Department for the Treatment of Substance Abuse and Mental Health Services, Israeli Ministry of Health, Jerusalem, Israel
- Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel
| | - Abraham Weizman
- The Laboratory of Molecular Psychiatry, Felsenstein Medical Research Center, Petah Tikva, Israel
- Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
- Research Unit, Geha Mental Health Center, Petah Tikva, Israel
| | - Gal Yadid
- Faculty of Life Sciences, Leslie and Gonda (Goldschmied) Multidisciplinary Brain Research Center, Bar Ilan University, Ramat Gan, Israel
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15
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Vlachou S. A Brief History and the Significance of the GABA B Receptor. Curr Top Behav Neurosci 2021; 52:1-17. [PMID: 34595739 DOI: 10.1007/7854_2021_264] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2023]
Abstract
γ-Aminobutyric acid (GABA) is the main inhibitory neurotransmitter in the brain. GABA type B (GABAB) receptors (GABABRs) are the only metabotropic G protein-coupled receptors for GABA and can be found distributed not only in the central nervous system, but also in the periphery. This chapter introduces important, fundamental knowledge related to GABABR function and the various potential therapeutic applications of the development of novel GABABR-active compounds, as documented through extensive studies presented in subsequent chapters of this Current Topic in Behavioral Neurosciences volume on the role of the neurobiology of GABABR function. The compounds that have received increased attention in the last few years compared to GABABR agonists and antagonists - the positive allosteric modulators - exhibit better pharmacological profiles and fewer side effects. As we continue to unveil the mystery of GABABRs at the molecular and cellular levels, we further understand the significance of these receptors. Future directions should aim for developing highly selective GABABR compounds for treating neuropsychiatric disorders and their symptomatology.
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Affiliation(s)
- Styliani Vlachou
- Neuropsychopharmacology Division, Behavioural Neuroscience Laboratory, School of Psychology, Faculty of Science and Health, Dublin City University, Dublin, Ireland.
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16
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GABA gets blood on its hands. Blood 2021; 137:723-724. [PMID: 33570609 DOI: 10.1182/blood.2020008772] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
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17
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Han B, He XH, Liu YQ, He G, Peng C, Li JL. Asymmetric organocatalysis: an enabling technology for medicinal chemistry. Chem Soc Rev 2021; 50:1522-1586. [PMID: 33496291 DOI: 10.1039/d0cs00196a] [Citation(s) in RCA: 192] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
The efficacy and synthetic versatility of asymmetric organocatalysis have contributed enormously to the field of organic synthesis since the early 2000s. As asymmetric organocatalytic methods mature, they have extended beyond the academia and undergone scale-up for the production of chiral drugs, natural products, and enantiomerically enriched bioactive molecules. This review provides a comprehensive overview of the applications of asymmetric organocatalysis in medicinal chemistry. A general picture of asymmetric organocatalytic strategies in medicinal chemistry is firstly presented, and the specific applications of these strategies in pharmaceutical synthesis are systematically described, with a focus on the preparation of antiviral, anticancer, neuroprotective, cardiovascular, antibacterial, and antiparasitic agents, as well as several miscellaneous bioactive agents. The review concludes with a discussion of the challenges, limitations and future prospects for organocatalytic asymmetric synthesis of medicinally valuable compounds.
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Affiliation(s)
- Bo Han
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Xiang-Hong He
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Yan-Qing Liu
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Gu He
- State Key Laboratory of Biotherapy and Cancer Centre, West China Hospital, Sichuan University, Chengdu 610041, China
| | - Cheng Peng
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China.
| | - Jun-Long Li
- State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu 611137, China. and Antibiotics Research and Re-evaluation Key Laboratory of Sichuan Province, Sichuan Industrial Institute of Antibiotics, School of Pharmacy, Chengdu University, Chengdu 610106, China.
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18
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GABA B Receptor Chemistry and Pharmacology: Agonists, Antagonists, and Allosteric Modulators. Curr Top Behav Neurosci 2021; 52:81-118. [PMID: 34036555 DOI: 10.1007/7854_2021_232] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
The GABAB receptors are metabotropic G protein-coupled receptors (GPCRs) that mediate the actions of the primary inhibitory neurotransmitter, γ-aminobutyric acid (GABA). In the CNS, GABA plays an important role in behavior, learning and memory, cognition, and stress. GABA is also located throughout the gastrointestinal (GI) tract and is involved in the autonomic control of the intestine and esophageal reflex. Consequently, dysregulated GABAB receptor signaling is associated with neurological, mental health, and gastrointestinal disorders; hence, these receptors have been identified as key therapeutic targets and are the focus of multiple drug discovery efforts for indications such as muscle spasticity disorders, schizophrenia, pain, addiction, and gastroesophageal reflex disease (GERD). Numerous agonists, antagonists, and allosteric modulators of the GABAB receptor have been described; however, Lioresal® (Baclofen; β-(4-chlorophenyl)-γ-aminobutyric acid) is the only FDA-approved drug that selectively targets GABAB receptors in clinical use; undesirable side effects, such as sedation, muscle weakness, fatigue, cognitive deficits, seizures, tolerance and potential for abuse, limit their therapeutic use. Here, we review GABAB receptor chemistry and pharmacology, presenting orthosteric agonists, antagonists, and positive and negative allosteric modulators, and highlight the therapeutic potential of targeting GABAB receptor modulation for the treatment of various CNS and peripheral disorders.
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19
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Shaye H, Stauch B, Gati C, Cherezov V. Molecular mechanisms of metabotropic GABA B receptor function. SCIENCE ADVANCES 2021; 7:7/22/eabg3362. [PMID: 34049877 PMCID: PMC8163086 DOI: 10.1126/sciadv.abg3362] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Accepted: 04/14/2021] [Indexed: 05/06/2023]
Abstract
Metabotropic γ-aminobutyric acid G protein-coupled receptors (GABAB) represent one of the two main types of inhibitory neurotransmitter receptors in the brain. These receptors act both pre- and postsynaptically by modulating the transmission of neuronal signals and are involved in a range of neurological diseases, from alcohol addiction to epilepsy. A series of recent cryo-EM studies revealed critical details of the activation mechanism of GABAB Structures are now available for the receptor bound to ligands with different modes of action, including antagonists, agonists, and positive allosteric modulators, and captured in different conformational states from the inactive apo to the fully active state bound to a G protein. These discoveries provide comprehensive insights into the activation of the GABAB receptor, which not only broaden our understanding of its structure, pharmacology, and physiological effects but also will ultimately facilitate the discovery of new therapeutic drugs and neuromodulators.
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Affiliation(s)
- Hamidreza Shaye
- Department of Chemistry, University of Southern California, Los Angeles, CA, USA
- Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA
| | - Benjamin Stauch
- Department of Chemistry, University of Southern California, Los Angeles, CA, USA
- Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA
| | - Cornelius Gati
- Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA
- Biosciences Division, SLAC National Accelerator Laboratory, Menlo Park, CA, USA
- Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
| | - Vadim Cherezov
- Department of Chemistry, University of Southern California, Los Angeles, CA, USA.
- Bridge Institute, Michelson Center for Convergent Biosciences, University of Southern California, Los Angeles, CA, USA
- Department of Biological Sciences, University of Southern California, Los Angeles, CA, USA
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20
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Sietmann J, Ong M, Mück‐Lichtenfeld C, Daniliuc CG, Wahl JM. Desymmetrization of Prochiral Cyclobutanones via Nitrogen Insertion: A Concise Route to Chiral γ-Lactams. Angew Chem Int Ed Engl 2021; 60:9719-9723. [PMID: 33538070 PMCID: PMC8252468 DOI: 10.1002/anie.202100642] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2021] [Indexed: 01/08/2023]
Abstract
Asymmetric access to γ-lactams is achieved via a cyclobutanone ring expansion using widely available (1S,2R)-1-amino-2-indanol for chiral induction. Mechanistic analysis of the key N,O-ketal rearrangement reveals a Curtin-Hammett scenario, which enables a downstream stereoinduction (up to 88:12 dr) and is corroborated by spectroscopic, crystallographic, and computational studies. In combination with an easy deprotection protocol, this operationally simple sequence allows the synthesis of a range of optically pure γ-lactams, including those bearing all-carbon quaternary stereocenters. In addition, the formal synthesis of drug molecules baclofen, brivaracetam, and pregabalin further demonstrates the synthetic utility and highlights the general applicability of the presented method.
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Affiliation(s)
- Jan Sietmann
- Organisch-Chemisches InstitutWestfälische Wilhelms-UniversitätCorrensstrasse 3648149MünsterGermany
| | - Mike Ong
- Organisch-Chemisches InstitutWestfälische Wilhelms-UniversitätCorrensstrasse 3648149MünsterGermany
| | | | - Constantin G. Daniliuc
- Organisch-Chemisches InstitutWestfälische Wilhelms-UniversitätCorrensstrasse 3648149MünsterGermany
| | - Johannes M. Wahl
- Organisch-Chemisches InstitutWestfälische Wilhelms-UniversitätCorrensstrasse 3648149MünsterGermany
- Department ChemieJohannes Gutenberg-UniversitätDuesbergweg 10–1455128MainzGermany
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21
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22
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de Sousa N, Santos D, Monteiro S, Silva N, Barreiro-Iglesias A, Salgado AJ. Role of Baclofen in Modulating Spasticity and Neuroprotection in Spinal Cord Injury. J Neurotrauma 2021; 39:249-258. [PMID: 33599153 DOI: 10.1089/neu.2020.7591] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Spinal cord injury (SCI) affects an estimated three million persons worldwide, with ∼180,000 new cases reported each year leading to severe motor and sensory functional impairments that affect personal and social behaviors. To date, no effective treatment has been made available to promote neurological recovery after SCI. Deficits in motor function is the most visible consequence of SCI; however, other secondary complications produce a significant impact on the welfare of patients with SCI. Spasticity is a neurological impairment that affects the control of muscle tone as a consequence of an insult, trauma, or injury to the central nervous system, such as SCI. The management of spasticity can be achieved through the combination of both nonpharmacological and pharmacological approaches. Baclofen is the most effective drug for spasticity treatment, and it can be administered both orally and intrathecally, depending on spasticity location and severity. Interestingly, recent data are revealing that baclofen can also play a role in neuroprotection after SCI. This new function of baclofen in the SCI scope is promising for the prospect of developing new pharmacological strategies to promote functional recovery in patients with SCI.
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Affiliation(s)
- Nídia de Sousa
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's Associate Lab, PT Government Associated Lab, Braga/Guimarães, Portugal
| | - Diogo Santos
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's Associate Lab, PT Government Associated Lab, Braga/Guimarães, Portugal
| | - Susana Monteiro
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's Associate Lab, PT Government Associated Lab, Braga/Guimarães, Portugal
| | - Nuno Silva
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's Associate Lab, PT Government Associated Lab, Braga/Guimarães, Portugal
| | | | - António J Salgado
- Life and Health Sciences Research Institute (ICVS), School of Medicine, University of Minho, Braga, Portugal.,ICVS/3B's Associate Lab, PT Government Associated Lab, Braga/Guimarães, Portugal
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23
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Sietmann J, Ong M, Mück‐Lichtenfeld C, Daniliuc CG, Wahl JM. Desymmetrisierung von prochiralen Cyclobutanonen via Stickstoffinsertion: Ein einfacher Zugang zu chiralen γ‐Lactamen. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202100642] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Affiliation(s)
- Jan Sietmann
- Organisch-Chemisches Institut Westfälische Wilhelms-Universität Corrensstraße 36 48149 Münster Deutschland
| | - Mike Ong
- Organisch-Chemisches Institut Westfälische Wilhelms-Universität Corrensstraße 36 48149 Münster Deutschland
| | - Christian Mück‐Lichtenfeld
- Organisch-Chemisches Institut Westfälische Wilhelms-Universität Corrensstraße 36 48149 Münster Deutschland
| | - Constantin G. Daniliuc
- Organisch-Chemisches Institut Westfälische Wilhelms-Universität Corrensstraße 36 48149 Münster Deutschland
| | - Johannes M. Wahl
- Organisch-Chemisches Institut Westfälische Wilhelms-Universität Corrensstraße 36 48149 Münster Deutschland
- Department Chemie Johannes Gutenberg-Universität Duesbergweg 10–14 55128 Mainz Deutschland
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24
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Yu S, Li J, Yao P, Feng J, Cui Y, Li J, Liu X, Wu Q, Lin J, Zhu D. Inverting the Enantiopreference of Nitrilase‐Catalyzed Desymmetric Hydrolysis of Prochiral Dinitriles by Reshaping the Binding Pocket with a Mirror‐Image Strategy. Angew Chem Int Ed Engl 2021. [DOI: 10.1002/ange.202012243] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022]
Affiliation(s)
- Shanshan Yu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jinlong Li
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Peiyuan Yao
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jinhui Feng
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Yunfeng Cui
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jianjiong Li
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Xiangtao Liu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Qiaqing Wu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jianping Lin
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Dunming Zhu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
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25
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Shao L, Elujoba-Bridenstine A, Zink KE, Sanchez LM, Cox BJ, Pollok KE, Sinn AL, Bailey BJ, Sims EC, Cooper SH, Broxmeyer HE, Pajcini KV, Tamplin OJ. The neurotransmitter receptor Gabbr1 regulates proliferation and function of hematopoietic stem and progenitor cells. Blood 2021; 137:775-787. [PMID: 32881992 PMCID: PMC7885825 DOI: 10.1182/blood.2019004415] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Accepted: 08/16/2020] [Indexed: 02/07/2023] Open
Abstract
Hematopoietic and nervous systems are linked via innervation of bone marrow (BM) niche cells. Hematopoietic stem/progenitor cells (HSPCs) express neurotransmitter receptors, such as the γ-aminobutyric acid (GABA) type B receptor subunit 1 (GABBR1), suggesting that HSPCs could be directly regulated by neurotransmitters like GABA that directly bind to GABBR1. We performed imaging mass spectrometry and found that the endogenous GABA molecule is regionally localized and concentrated near the endosteum of the BM niche. To better understand the role of GABBR1 in regulating HSPCs, we generated a constitutive Gabbr1-knockout mouse model. Analysis revealed that HSPC numbers were significantly reduced in the BM compared with wild-type littermates. Moreover, Gabbr1-null hematopoietic stem cells had diminished capacity to reconstitute irradiated recipients in a competitive transplantation model. Gabbr1-null HSPCs were less proliferative under steady-state conditions and upon stress. Colony-forming unit assays demonstrated that almost all Gabbr1-null HSPCs were in a slow or noncycling state. In vitro differentiation of Gabbr1-null HSPCs in cocultures produced fewer overall cell numbers with significant defects in differentiation and expansion of the B-cell lineage. To determine whether a GABBR1 agonist could stimulate human umbilical cord blood (UCB) HSPCs, we performed brief ex vivo treatment prior to transplant into immunodeficient mice, with significant increases in long-term engraftment of HSPCs compared with GABBR1 antagonist or vehicle treatments. Our results indicate a direct role for GABBR1 in HSPC proliferation, and identify a potential target to improve HSPC engraftment in clinical transplantation.
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Affiliation(s)
- Lijian Shao
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL
- Department of Occupational Health and Toxicology, School of Public Health, Nanchang University, Nanchang, People's Republic of China
| | - Adedamola Elujoba-Bridenstine
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI
| | - Katherine E Zink
- Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL
| | - Laura M Sanchez
- Department of Pharmaceutical Sciences, University of Illinois at Chicago, Chicago, IL
| | - Brian J Cox
- Department of Physiology and
- Department of Obstetrics and Gynaecology, University of Toronto, Toronto, ON, Canada; and
| | - Karen E Pollok
- Department of Pharmacology and Toxicology
- Department of Pediatrics
- Melvin and Bren Simon Cancer Center, and
| | | | | | | | - Scott H Cooper
- Department of Microbiology and Immunology, School of Medicine, Indiana University, Indianapolis, IN
| | - Hal E Broxmeyer
- Melvin and Bren Simon Cancer Center, and
- Department of Microbiology and Immunology, School of Medicine, Indiana University, Indianapolis, IN
| | | | - Owen J Tamplin
- Department of Pharmacology, University of Illinois at Chicago, Chicago, IL
- Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI
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26
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Liao LL, Cao GM, Jiang YX, Jin XH, Hu XL, Chruma JJ, Sun GQ, Gui YY, Yu DG. α-Amino Acids and Peptides as Bifunctional Reagents: Carbocarboxylation of Activated Alkenes via Recycling CO2. J Am Chem Soc 2021; 143:2812-2821. [DOI: 10.1021/jacs.0c11896] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Affiliation(s)
- Li-Li Liao
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
| | - Guang-Mei Cao
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
| | - Yuan-Xu Jiang
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
| | - Xing-Hao Jin
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
| | - Xin-Long Hu
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
| | - Jason J. Chruma
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
- Department of Chemistry, University of Virginia, Charlottesville, Virginia 22904-4319, United States
| | - Guo-Quan Sun
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
| | - Yong-Yuan Gui
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
- College of Chemistry and Materials Science, Sichuan Normal University, Chengdu 610068, People’s Republic of China
| | - Da-Gang Yu
- Key Laboratory of Green Chemistry & Technology of Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, People’s Republic of China
- Beijing National Laboratory for Molecular Sciences, Beijing 100190, People’s Republic of China
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Yu S, Li J, Yao P, Feng J, Cui Y, Li J, Liu X, Wu Q, Lin J, Zhu D. Inverting the Enantiopreference of Nitrilase‐Catalyzed Desymmetric Hydrolysis of Prochiral Dinitriles by Reshaping the Binding Pocket with a Mirror‐Image Strategy. Angew Chem Int Ed Engl 2020; 60:3679-3684. [DOI: 10.1002/anie.202012243] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 10/19/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Shanshan Yu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jinlong Li
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Peiyuan Yao
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jinhui Feng
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Yunfeng Cui
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jianjiong Li
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Xiangtao Liu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Qiaqing Wu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Jianping Lin
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
| | - Dunming Zhu
- National Technology Innovation Center of Synthetic Biology National Engineering Laboratory for Industrial Enzymes and Tianjin Engineering Research Center of Biocatalytic Technology Tianjin Institute of Industrial Biotechnology Chinese Academy of Sciences 32 Xi Qi Dao, Tianjin Airport Economic Area Tianjin 300308 P. R. China
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Ammari R, Broberger C. Pre- and post-synaptic modulation by GABA B receptors of rat neuroendocrine dopamine neurones. J Neuroendocrinol 2020; 32:e12881. [PMID: 32803906 DOI: 10.1111/jne.12881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 05/22/2020] [Accepted: 06/05/2020] [Indexed: 12/17/2022]
Abstract
The secretion of prolactin from the pituitary is negatively controlled by tuberoinfundibular dopamine (TIDA) neurones. The electrical properties of TIDA cells have recently been identified as a modulatory target of neurotransmitters and hormones in the lactotrophic axis. The role of the GABAB receptor in this control has received little attention, yet is of particular interest because it may act as a TIDA neurone autoreceptor. Here, this issue was explored in a spontaneously active rat TIDA in vitro slice preparation using whole-cell recordings. Application of the GABAB receptor agonist, baclofen, dose-dependently slowed down or abolished the network oscillations typical of this preparation. Pharmacological manipulations identify the underlying mechanism as an outward current mediated by G-protein-coupled inwardly rectifying K+ -like channels. In addition to this postsynaptic modulation, we describe a presynaptic modulation where GABAB receptors restrain the release of glutamate and GABA onto TIDA neurones. Our data identify both pre- and postsynaptic modulation of TIDA neurones by GABAB receptors that may play a role in the neuronal network control of pituitary prolactin secretion and lactation.
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Affiliation(s)
- Rachida Ammari
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
| | - Christian Broberger
- Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden
- Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden
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29
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Evenseth LSM, Gabrielsen M, Sylte I. The GABA B Receptor-Structure, Ligand Binding and Drug Development. Molecules 2020; 25:molecules25133093. [PMID: 32646032 PMCID: PMC7411975 DOI: 10.3390/molecules25133093] [Citation(s) in RCA: 64] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Revised: 07/02/2020] [Accepted: 07/06/2020] [Indexed: 11/17/2022] Open
Abstract
The γ-aminobutyric acid (GABA) type B receptor (GABAB-R) belongs to class C of the G-protein coupled receptors (GPCRs). Together with the GABAA receptor, the receptor mediates the neurotransmission of GABA, the main inhibitory neurotransmitter in the central nervous system (CNS). In recent decades, the receptor has been extensively studied with the intention being to understand pathophysiological roles, structural mechanisms and develop drugs. The dysfunction of the receptor is linked to a broad variety of disorders, including anxiety, depression, alcohol addiction, memory and cancer. Despite extensive efforts, few compounds are known to target the receptor, and only the agonist baclofen is approved for clinical use. The receptor is a mandatory heterodimer of the GABAB1 and GABAB2 subunits, and each subunit is composed of an extracellular Venus Flytrap domain (VFT) and a transmembrane domain of seven α-helices (7TM domain). In this review, we briefly present the existing knowledge about the receptor structure, activation and compounds targeting the receptor, emphasizing the role of the receptor in previous and future drug design and discovery efforts.
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Affiliation(s)
- Linn Samira Mari Evenseth
- Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway
| | - Mari Gabrielsen
- Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway
| | - Ingebrigt Sylte
- Molecular Pharmacology and Toxicology, Department of Medical Biology, Faculty of Health Sciences, UiT The Arctic University of Norway, NO-9037 Tromsø, Norway
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Abstract
Baclofen, β-(4-chlorophenyl)-γ-aminobutyric acid, holds a unique position in neuroscience, remaining the only U.S. Food and Drug Administration (FDA) approved GABAB agonist. While intended to be a more brain penetrant, i.e, ability to cross the blood-brain barrier (BBB), version of GABA (γ-aminobutyric acid) for the potential treatment of epilepsy, baclofen's highly efficacious muscle relaxant properties led to its approval, as a racemate, for the treatment of spasticity. Interestingly, baclofen received FDA approval before its receptor, GABAB, was discovered and its exact mechanism of action was known. In recent times, baclofen has a myriad of off-label uses, with the treatment for alcohol abuse and drug addiction garnering a great deal of attention. This Review aims to capture the >60 year legacy of baclofen by walking through the history, pharmacology, synthesis, drug metabolism, routes of administration, and societal impact of this Classic in chemical neuroscience.
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Affiliation(s)
- Caitlin N. Kent
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
| | - Charlotte Park
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
| | - Craig W. Lindsley
- Warren Center for Neuroscience Drug Discovery, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
- Department of Chemistry, Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States
- Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232, United States
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31
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GABA B receptors: modulation of thalamocortical dynamics and synaptic plasticity. Neuroscience 2020; 456:131-142. [PMID: 32194227 DOI: 10.1016/j.neuroscience.2020.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Revised: 03/05/2020] [Accepted: 03/06/2020] [Indexed: 01/03/2023]
Abstract
GABAB-receptors (GABAB-Rs) are metabotropic, G protein-coupled receptors for the neurotransmitter GABA. Their activation induces slow inhibitory control of the neuronal excitability mediated by pre- and postsynaptic inhibition. Presynaptically GABAB-Rs reduce GABA and glutamate release inhibiting presynaptic Ca2+ channels in both inhibitory and excitatory synapses while postsynaptic GABAB-Rs induce robust slow hyperpolarization by the activation of K+ channels. GABAB-Rs are activated by non-synaptic or volume transmission, which requires high levels of GABA release, either by the simultaneous discharge of GABAergic interneurons or very intense discharges in the thalamus or by means of the activation of a neurogliaform interneurons in the cortex. The main receptor subunits GABAB1a, GABAB1b and GABAB2 are strongly expressed in neurons and glial cells throughout the central nervous system and GABAB-R activation is related to many neuronal processes such as the modulation of rhythmic activity in several brain regions. In the thalamus, GABAB-Rs modulate the generation of the main thalamic rhythm, spindle waves. In the cerebral cortex, GABAB-Rs also modulate the most prominent emergent oscillatory activity-slow oscillations-as well as faster oscillations like gamma frequency. Further, recent studies evaluating the complexity expressed by the cortical network, a parameter associated with consciousness levels, have found that GABAB-Rs enhance this complexity, while their blockade decreases it. This review summarizes the current results on how the activation of GABAB-Rs affects the interchange of information between brain areas by controlling rhythmicity as well as synaptic plasticity.
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32
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Assad S, Sabala R, Jiménez J, Sansinenea E, Ortiz A. Diastereoselective conjugate addition of organocuprates to N-[4-(Dibenzylaminobutenoyl)]oxazolidinone. Synthesis of chiral β-substituted γ-aminoacids. Tetrahedron Lett 2019. [DOI: 10.1016/j.tetlet.2019.05.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
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Avoli M. Inhibition, oscillations and focal seizures: An overview inspired by some historical notes. Neurobiol Dis 2019; 130:104478. [PMID: 31125597 DOI: 10.1016/j.nbd.2019.104478] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
GABA (i.e., γ-amino-butyric acid) is the main inhibitory neurotransmitter in the adult mammalian brain. Once released from inhibitory cells, it activates pre- and post-synaptic GABA receptors that have been categorized into type A and type B. GABAA receptors open ionotropic anionic channels while GABAB receptors are metabotropic, acting through second messengers. In the 1980s, decreased GABA receptor signaling was considered an appealing factor in making cortical neurons generate synchronous epileptiform oscillations and thus a good, perhaps obvious, candidate for causing focal epileptic disorders. However, studies published during the last four decades have demonstrated that interneuron firing - which causes GABA release and thus GABAA receptor activation - can lead to the generation of both physiological (e.g., theta and gamma oscillations or sharp wave-ripples) and pathological oscillations including focal interictal spikes, high frequency oscillations and seizures. Taken together, the reviews published in this special issue of Neurobiology of Disease highlight the key role of inhibition, and in particular of GABAA receptor signaling, in neuronal network functions under physiological and pathological conditions that include epilepsy and Alzheimer's disease.
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Affiliation(s)
- Massimo Avoli
- Montreal Neurological Institute, McGill University, Montreal, H3A 2B4, QC, Canada; Department of Neurology & Neurosurgery, McGill University, Montreal, H3A 2B4, QC, Canada; Department of Experimental Medicine, Facoltà di Medicina e Odontoiatria, Sapienza University of Rome, 00185 Roma, Italy; Department of Physiology, McGill University, Montreal, H3A 2B4, QC, Canada.
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Assembling of medium/long chain-based β-arylated unnatural amino acid derivatives via the Pd(II)-catalyzed sp3 β-C-H arylation and a short route for rolipram-type derivatives. Tetrahedron 2019. [DOI: 10.1016/j.tet.2019.03.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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35
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Fogaça MV, Duman RS. Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front Cell Neurosci 2019. [PMID: 30914923 DOI: 10.3389/fncel.2019.00087/full] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/15/2023] Open
Abstract
Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation-inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.
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Affiliation(s)
- Manoela V Fogaça
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
| | - Ronald S Duman
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
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36
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Das I, Estevez MA, Sarkar AA, Banerjee-Basu S. A multifaceted approach for analyzing complex phenotypic data in rodent models of autism. Mol Autism 2019; 10:11. [PMID: 30911366 PMCID: PMC6417187 DOI: 10.1186/s13229-019-0263-7] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2018] [Accepted: 02/21/2019] [Indexed: 12/26/2022] Open
Abstract
Autism (MIM 209850) is a multifactorial disorder with a broad clinical presentation. A number of high-confidence ASD risk genes are known; however, the contribution of non-genetic environmental factors towards ASD remains largely uncertain. Here, we present a bioinformatics resource of genetic and induced models of ASD developed using a shared annotation platform. Using this data, we depict the intricate trends in the research approaches to analyze rodent models of ASD. We identify the top 30 most frequently studied phenotypes extracted from rodent models of ASD based on 787 publications. As expected, many of these include animal model equivalents of the “core” phenotypes associated with ASD, such as impairments in social behavior and repetitive behavior, as well as several comorbid features of ASD including anxiety, seizures, and motor-control deficits. These phenotypes have also been studied in models based on a broad range of environmental inducers present in the database, of which gestational exposure to valproic acid (VPA) and maternal immune activation models comprising lipopolysaccharide (LPS) and poly I:C are the most studied. In our unique dataset of rescue models, we identify 24 pharmaceutical agents tested on established models derived from various ASD genes and CNV loci for their efficacy in mitigating symptoms relevant for ASD. As a case study, we analyze a large collection of Shank3 mouse models providing a high-resolution view of the in vivo role of this high-confidence ASD gene, which is the gateway towards understanding and dissecting the heterogeneous phenotypes seen in single-gene models of ASD. The trends described in this study could be useful for researchers to compare ASD models and to establish a complete profile for all relevant animal models in ASD research.
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Affiliation(s)
- Ishita Das
- MindSpec Inc., 8280 Greensboro Drive, Suite 150, McLean, VA 22102 USA
| | - Marcel A Estevez
- MindSpec Inc., 8280 Greensboro Drive, Suite 150, McLean, VA 22102 USA
| | - Anjali A Sarkar
- MindSpec Inc., 8280 Greensboro Drive, Suite 150, McLean, VA 22102 USA
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37
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Fogaça MV, Duman RS. Cortical GABAergic Dysfunction in Stress and Depression: New Insights for Therapeutic Interventions. Front Cell Neurosci 2019; 13:87. [PMID: 30914923 PMCID: PMC6422907 DOI: 10.3389/fncel.2019.00087] [Citation(s) in RCA: 231] [Impact Index Per Article: 38.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Accepted: 02/20/2019] [Indexed: 12/14/2022] Open
Abstract
Major depressive disorder (MDD) is a debilitating illness characterized by neuroanatomical and functional alterations in limbic structures, notably the prefrontal cortex (PFC), that can be precipitated by exposure to chronic stress. For decades, the monoaminergic deficit hypothesis of depression provided the conceptual framework to understand the pathophysiology of MDD. However, accumulating evidence suggests that MDD and chronic stress are associated with an imbalance of excitation-inhibition (E:I) within the PFC, generated by a deficit of inhibitory synaptic transmission onto principal glutamatergic neurons. MDD patients and chronically stressed animals show a reduction in GABA and GAD67 levels in the brain, decreased expression of GABAergic interneuron markers, and alterations in GABAA and GABAB receptor levels. Moreover, genetically modified animals with deletion of specific GABA receptors subunits or interneuron function show depressive-like behaviors. Here, we provide further evidence supporting the role of cortical GABAergic interneurons, mainly somatostatin- and parvalbumin-expressing cells, required for the optimal E:I balance in the PFC and discuss how the malfunction of these cells can result in depression-related behaviors. Finally, considering the relatively low efficacy of current available medications, we review new fast-acting pharmacological approaches that target the GABAergic system to treat MDD. We conclude that deficits in cortical inhibitory neurotransmission and interneuron function resulting from chronic stress exposure can compromise the integrity of neurocircuits and result in the development of MDD and other stress-related disorders. Drugs that can establish a new E:I balance in the PFC by targeting the glutamatergic and GABAergic systems show promising as fast-acting antidepressants and represent breakthrough strategies for the treatment of depression.
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Affiliation(s)
- Manoela V Fogaça
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
| | - Ronald S Duman
- Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States
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38
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Zurawski Z, Yim YY, Alford S, Hamm HE. The expanding roles and mechanisms of G protein-mediated presynaptic inhibition. J Biol Chem 2019; 294:1661-1670. [PMID: 30710014 PMCID: PMC6364771 DOI: 10.1074/jbc.tm118.004163] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/28/2023] Open
Abstract
Throughout the past five decades, tremendous advancements have been made in our understanding of G protein signaling and presynaptic inhibition, many of which were published in the Journal of Biological Chemistry under the tenure of Herb Tabor as Editor-in-Chief. Here, we identify these critical advances, including the formulation of the ternary complex model of G protein-coupled receptor signaling and the discovery of Gβγ as a critical signaling component of the heterotrimeric G protein, along with the nature of presynaptic inhibition and its physiological role. We provide an overview for the discovery and physiological relevance of the two known Gβγ-mediated mechanisms for presynaptic inhibition: first, the action of Gβγ on voltage-gated calcium channels to inhibit calcium influx to the presynaptic active zone and, second, the direct binding of Gβγ to the SNARE complex to displace synaptotagmin downstream of calcium entry, which has been demonstrated to be important in neurons and secretory cells. These two mechanisms act in tandem with each other in a synergistic manner to provide more complete spatiotemporal control over neurotransmitter release.
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Affiliation(s)
- Zack Zurawski
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600; Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois 60612-7308
| | - Yun Young Yim
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600
| | - Simon Alford
- Department of Anatomy and Cell Biology, University of Illinois, Chicago, Illinois 60612-7308
| | - Heidi E Hamm
- Department of Pharmacology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-6600.
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Cunningham JA, Jelic S. Baclofen Withdrawal: A Cause of Prolonged Fever in the Intensive Care Unit. Anaesth Intensive Care 2019; 33:534-7. [PMID: 16119501 DOI: 10.1177/0310057x0503300421] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
We report a case of baclofen withdrawal syndrome resulting from oral baclofen underdosing. A 24-year-old woman with type 1 neurofibromatosis receiving long-term baclofen therapy was admitted with presumed pneumonia which was successfully treated with antibiotics. The patient continued to have fever and autonomic instability without evidence of infection which entirely resolved within 24 hours of reinstitution of full preadmission dosing of oral baclofen. Baclofen withdrawal syndrome resulting from underdosing of oral baclofen should be considered as a potential source of prolonged fever in the intensive care unit.
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Affiliation(s)
- J A Cunningham
- Division of Pulmonary, Allergy and Critical Care Medicine, Columbia University College of Physicians and Surgeons, New York 10032, USA
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40
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Yu S, Yao P, Li J, Feng J, Wu Q, Zhu D. Improving the catalytic efficiency and stereoselectivity of a nitrilase from Synechocystis sp. PCC6803 by semi-rational engineering en route to chiral γ-amino acids. Catal Sci Technol 2019. [DOI: 10.1039/c8cy02455c] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
Simultaneously improving activity and stereoselectivity of a nitrilase to catalyze the desymmetrization of 3-substituted glutaronitriles is presented.
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Affiliation(s)
- Shanshan Yu
- National Engineering Laboratory for Industrial Enzymes
- Tianjin Engineering Research Center of Biocatalytic Technology
- Tianjin Institute of Industrial Biotechnology
- Chinese Academy of Sciences
- Tianjin 300308
| | - Peiyuan Yao
- National Engineering Laboratory for Industrial Enzymes
- Tianjin Engineering Research Center of Biocatalytic Technology
- Tianjin Institute of Industrial Biotechnology
- Chinese Academy of Sciences
- Tianjin 300308
| | - Jinlong Li
- National Engineering Laboratory for Industrial Enzymes
- Tianjin Engineering Research Center of Biocatalytic Technology
- Tianjin Institute of Industrial Biotechnology
- Chinese Academy of Sciences
- Tianjin 300308
| | - Jinhui Feng
- National Engineering Laboratory for Industrial Enzymes
- Tianjin Engineering Research Center of Biocatalytic Technology
- Tianjin Institute of Industrial Biotechnology
- Chinese Academy of Sciences
- Tianjin 300308
| | - Qiaqing Wu
- National Engineering Laboratory for Industrial Enzymes
- Tianjin Engineering Research Center of Biocatalytic Technology
- Tianjin Institute of Industrial Biotechnology
- Chinese Academy of Sciences
- Tianjin 300308
| | - Dunming Zhu
- National Engineering Laboratory for Industrial Enzymes
- Tianjin Engineering Research Center of Biocatalytic Technology
- Tianjin Institute of Industrial Biotechnology
- Chinese Academy of Sciences
- Tianjin 300308
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41
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Abstract
γ-aminobutyric acid has become one of the most widely known neurotransmitter molecules in the brain over the last 50 years, recognised for its pivotal role in inhibiting neural excitability. It emerged from studies of crustacean muscle and neurons before its significance to the mammalian nervous system was appreciated. Now, after five decades of investigation, we know that most neurons are γ-aminobutyric-acid-sensitive, it is a cornerstone of neural physiology and dysfunction to γ-aminobutyric acid signalling is increasingly documented in a range of neurological diseases. In this review, we briefly chart the neurodevelopment of γ-aminobutyric acid and its two major receptor subtypes: the γ-aminobutyric acidA and γ-aminobutyric acidB receptors, starting from the humble invertebrate origins of being an 'interesting molecule' acting at a single γ-aminobutyric acid receptor type, to one of the brain's most important neurochemical components and vital drug targets for major therapeutic classes of drugs. We document the period of molecular cloning and the explosive influence this had on the field of neuroscience and pharmacology up to the present day and the production of atomic γ-aminobutyric acidA and γ-aminobutyric acidB receptor structures. γ-Aminobutyric acid is no longer a humble molecule but the instigator of rich and powerful signalling processes that are absolutely vital for healthy brain function.
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Affiliation(s)
- Trevor G Smart
- Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK
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42
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Impaired Hypothalamic Regulation of Sympathetic Outflow in Primary Hypertension. Neurosci Bull 2018; 35:124-132. [PMID: 30506315 DOI: 10.1007/s12264-018-0316-5] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2018] [Accepted: 11/01/2018] [Indexed: 01/01/2023] Open
Abstract
The hypothalamic paraventricular nucleus (PVN) is a crucial region involved in maintaining homeostasis through the regulation of cardiovascular, neuroendocrine, and other functions. The PVN provides a dominant source of excitatory drive to the sympathetic outflow through innervation of the brainstem and spinal cord in hypertension. We discuss current findings on the role of the PVN in the regulation of sympathetic output in both normotensive and hypertensive conditions. The PVN seems to play a major role in generating the elevated sympathetic vasomotor activity that is characteristic of multiple forms of hypertension, including primary hypertension in humans. Recent studies in the spontaneously hypertensive rat model have revealed an imbalance of inhibitory and excitatory synaptic inputs to PVN pre-sympathetic neurons as indicated by impaired inhibitory and enhanced excitatory synaptic inputs in hypertension. This imbalance of inhibitory and excitatory synaptic inputs in the PVN forms the basis for elevated sympathetic outflow in hypertension. In this review, we discuss the disruption of balance between glutamatergic and GABAergic inputs and the associated cellular and molecular alterations as mechanisms underlying the hyperactivity of PVN pre-sympathetic neurons in hypertension.
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Zhu M, Wang D, Xie M, Qu G, Guo H. Enantioselective Friedel–Crafts Alkylation Reactions of β‐Naphthols with Donor–Acceptor Aminocyclopropanes. Chemistry 2018; 24:15512-15516. [DOI: 10.1002/chem.201804032] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2018] [Indexed: 02/03/2023]
Affiliation(s)
- Man Zhu
- School of Chemistry and Chemical Engineering Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation Collaborative Innovation Center of Henan Province for, Green Manufacturing of Fine Chemicals Henan Normal University Xinxiang Henan 453007 China
| | - Dong‐Chao Wang
- School of Chemistry and Chemical Engineering Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation Collaborative Innovation Center of Henan Province for, Green Manufacturing of Fine Chemicals Henan Normal University Xinxiang Henan 453007 China
| | - Ming‐Sheng Xie
- School of Chemistry and Chemical Engineering Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation Collaborative Innovation Center of Henan Province for, Green Manufacturing of Fine Chemicals Henan Normal University Xinxiang Henan 453007 China
| | - Gui‐Rong Qu
- School of Chemistry and Chemical Engineering Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation Collaborative Innovation Center of Henan Province for, Green Manufacturing of Fine Chemicals Henan Normal University Xinxiang Henan 453007 China
| | - Hai‐Ming Guo
- School of Chemistry and Chemical Engineering Henan Key Laboratory of Organic Functional Molecules and Drugs Innovation Collaborative Innovation Center of Henan Province for, Green Manufacturing of Fine Chemicals Henan Normal University Xinxiang Henan 453007 China
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Ma J, Lin J, Zhao L, Harms K, Marsch M, Xie X, Meggers E. Synthesis of β-Substituted γ-Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis. Angew Chem Int Ed Engl 2018; 57:11193-11197. [DOI: 10.1002/anie.201804040] [Citation(s) in RCA: 68] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2018] [Indexed: 12/15/2022]
Affiliation(s)
- Jiajia Ma
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Jiahui Lin
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Lifang Zhao
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Klaus Harms
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Michael Marsch
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Xiulan Xie
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Eric Meggers
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
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Ma J, Lin J, Zhao L, Harms K, Marsch M, Xie X, Meggers E. Synthesis of β-Substituted γ-Aminobutyric Acid Derivatives through Enantioselective Photoredox Catalysis. Angew Chem Int Ed Engl 2018. [DOI: 10.1002/ange.201804040] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Jiajia Ma
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Jiahui Lin
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Lifang Zhao
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Klaus Harms
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Michael Marsch
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Xiulan Xie
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
| | - Eric Meggers
- Fachbereich Chemie; Philipps-Universität Marburg; Hans-Meerwein-Strasse 4 35043 Marburg Germany
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46
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Frangaj A, Fan QR. Structural biology of GABA B receptor. Neuropharmacology 2018; 136:68-79. [PMID: 29031577 PMCID: PMC5897222 DOI: 10.1016/j.neuropharm.2017.10.011] [Citation(s) in RCA: 65] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2017] [Revised: 10/09/2017] [Accepted: 10/11/2017] [Indexed: 11/17/2022]
Abstract
Metabotropic GABAB receptor is a G protein-coupled receptor (GPCR) that mediates slow and prolonged inhibitory neurotransmission in the brain. It functions as a constitutive heterodimer composed of the GABAB1 and GABAB2 subunits. Each subunit contains three domains; the extracellular Venus flytrap module, seven-helix transmembrane region and cytoplasmic tail. In recent years, the three-dimensional structures of GABAB receptor extracellular and intracellular domains have been elucidated. These structures reveal the molecular basis of ligand recognition, receptor heterodimerization and receptor activation. Here we provide a brief review of the GABAB receptor structures, with an emphasis on describing the different ligand-bound states of the receptor. We will also compare these with the known structures of related GPCRs to shed light on the molecular mechanisms of activation and regulation in the GABAB system, as well as GPCR dimers in general. This article is part of the "Special Issue Dedicated to Norman G. Bowery".
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Affiliation(s)
- Aurel Frangaj
- Department of Pharmacology, Columbia University, New York, NY 10032, USA
| | - Qing R Fan
- Department of Pharmacology, Columbia University, New York, NY 10032, USA; Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA.
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Olsen RW. GABA A receptor: Positive and negative allosteric modulators. Neuropharmacology 2018; 136:10-22. [PMID: 29407219 PMCID: PMC6027637 DOI: 10.1016/j.neuropharm.2018.01.036] [Citation(s) in RCA: 215] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 01/23/2018] [Accepted: 01/25/2018] [Indexed: 12/11/2022]
Abstract
gamma-Aminobutyric acid (GABA)-mediated inhibitory neurotransmission and the gene products involved were discovered during the mid-twentieth century. Historically, myriad existing nervous system drugs act as positive and negative allosteric modulators of these proteins, making GABA a major component of modern neuropharmacology, and suggesting that many potential drugs will be found that share these targets. Although some of these drugs act on proteins involved in synthesis, degradation, and membrane transport of GABA, the GABA receptors Type A (GABAAR) and Type B (GABABR) are the targets of the great majority of GABAergic drugs. This discovery is due in no small part to Professor Norman Bowery. Whereas the topic of GABABR is appropriately emphasized in this special issue, Norman Bowery also made many insights into GABAAR pharmacology, the topic of this article. GABAAR are members of the ligand-gated ion channel receptor superfamily, a chloride channel family of a dozen or more heteropentameric subtypes containing 19 possible different subunits. These subtypes show different brain regional and subcellular localization, age-dependent expression, and potential for plastic changes with experience including drug exposure. Not only are GABAAR the targets of agonist depressants and antagonist convulsants, but most GABAAR drugs act at other (allosteric) binding sites on the GABAAR proteins. Some anxiolytic and sedative drugs, like benzodiazepine and related drugs, act on GABAAR subtype-dependent extracellular domain sites. General anesthetics including alcohols and neurosteroids act at GABAAR subunit-interface trans-membrane sites. Ethanol at high anesthetic doses acts on GABAAR subtype-dependent trans-membrane domain sites. Ethanol at low intoxicating doses acts at GABAAR subtype-dependent extracellular domain sites. Thus GABAAR subtypes possess pharmacologically specific receptor binding sites for a large group of different chemical classes of clinically important neuropharmacological agents. This article is part of the "Special Issue Dedicated to Norman G. Bowery".
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Affiliation(s)
- Richard W Olsen
- Department of Molecular & Medical Pharmacology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
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Sadeghi M, Carstens BB, Callaghan BP, Daniel JT, Tae HS, O’Donnell T, Castro J, Brierley SM, Adams DJ, Craik DJ, Clark RJ. Structure-Activity Studies Reveal the Molecular Basis for GABA B-Receptor Mediated Inhibition of High Voltage-Activated Calcium Channels by α-Conotoxin Vc1.1. ACS Chem Biol 2018; 13:1577-1587. [PMID: 29746088 DOI: 10.1021/acschembio.8b00190] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
α-Conotoxins are disulfide-bonded peptides from cone snail venoms and are characterized by their affinity for nicotinic acetylcholine receptors (nAChR). Several α-conotoxins with distinct selectivity for nAChR subtypes have been identified as potent analgesics in animal models of chronic pain. However, a number of α-conotoxins have been shown to inhibit N-type calcium channel currents in rodent dissociated dorsal root ganglion (DRG) neurons via activation of G protein-coupled GABAB receptors (GABABR). Therefore, it is unclear whether activation of GABABR or inhibition of α9α10 nAChRs is the analgesic mechanism. To investigate the mechanisms by which α-conotoxins provide analgesia, we synthesized a suite of Vc1.1 analogues where all residues, except the conserved cysteines, in Vc1.1 were individually replaced by alanine (A), lysine (K), and aspartic acid (D). Our results show that the amino acids in the first loop play an important role in binding of the peptide to the receptor, whereas those in the second loop play an important role for the selectivity of the peptide for the GABABR over α9α10 nAChRs. We designed a cVc1.1 analogue that is >8000-fold selective for GABABR-mediated inhibition of high voltage-activated (HVA) calcium channels over α9α10 nAChRs and show that it is analgesic in a mouse model of chronic visceral hypersensitivity (CVH). cVc1.1[D11A,E14A] caused dose-dependent inhibition of colonic nociceptors with greater efficacy in ex vivo CVH colonic nociceptors relative to healthy colonic nociceptors. These findings suggest that selectively targeting GABABR-mediated HVA calcium channel inhibition by α-conotoxins could be effective for the treatment of chronic visceral pain.
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Affiliation(s)
- Mahsa Sadeghi
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia
| | - Bodil B. Carstens
- The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland 4072, Australia
| | - Brid P. Callaghan
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia
- The University of Queensland, School of Biomedical Sciences, Brisbane, Queensland 4072, Australia
| | - James T. Daniel
- The University of Queensland, School of Biomedical Sciences, Brisbane, Queensland 4072, Australia
| | - Han-Shen Tae
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia
| | - Tracey O’Donnell
- Visceral Pain Research Group, Human Physiology, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, Southern Australia 5000, Australia
| | - Joel Castro
- Visceral Pain Research Group, Human Physiology, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, Southern Australia 5000, Australia
| | - Stuart M. Brierley
- Visceral Pain Research Group, Human Physiology, Centre for Neuroscience, College of Medicine and Public Health, Flinders University, Bedford Park, South Australia 5042, Australia
- Centre for Nutrition and Gastrointestinal Diseases, Discipline of Medicine, University of Adelaide, South Australian Health and Medical Research Institute (SAHMRI), North Terrace, Adelaide, Southern Australia 5000, Australia
| | - David J. Adams
- Illawarra Health and Medical Research Institute (IHMRI), University of Wollongong, Wollongong, New South Wales 2522, Australia
| | - David J. Craik
- The University of Queensland, Institute for Molecular Bioscience, Brisbane, Queensland 4072, Australia
| | - Richard J. Clark
- The University of Queensland, School of Biomedical Sciences, Brisbane, Queensland 4072, Australia
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Jacobson LH, Vlachou S, Slattery DA, Li X, Cryan JF. The Gamma-Aminobutyric Acid B Receptor in Depression and Reward. Biol Psychiatry 2018; 83:963-976. [PMID: 29759132 DOI: 10.1016/j.biopsych.2018.02.006] [Citation(s) in RCA: 54] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2017] [Revised: 01/14/2018] [Accepted: 02/06/2018] [Indexed: 12/31/2022]
Abstract
The metabotropic gamma-aminobutyric acid B (GABAB) receptor was the first described obligate G protein-coupled receptor heterodimer and continues to set the stage for discoveries in G protein-coupled receptor signaling complexity. In this review, dedicated to the life and work of Athina Markou, we explore the role of GABAB receptors in depression, reward, and the convergence of these domains in anhedonia, a shared symptom of major depressive disorder and withdrawal from drugs of abuse. GABAB receptor expression and function are enhanced by antidepressants and reduced in animal models of depression. Generally, GABAB receptor antagonists are antidepressant-like and agonists are pro-depressive. Exceptions to this rule likely reflect the differential influence of GABAB1 isoforms in depression-related behavior and neurobiology, including the anhedonic effects of social stress. A wealth of data implicate GABAB receptors in the rewarding effects of drugs of abuse. We focus on nicotine as an example. GABAB receptor activation attenuates, and deactivation enhances, nicotine reward and associated neurobiological changes. In nicotine withdrawal, however, GABAB receptor agonists, antagonists, and positive allosteric modulators enhance anhedonia, perhaps owing to differential effects of GABAB1 isoforms on the dopaminergic system. Nicotine cue-induced reinstatement is more reliably attenuated by GABAB receptor activation. Separation of desirable and undesirable side effects of agonists is achievable with positive allosteric modulators, which are poised to enter clinical studies for drug abuse. GABAB1 isoforms are key to understanding the neurobiology of anhedonia, whereas allosteric modulators may offer a mechanism for targeting specific brain regions and processes associated with reward and depression.
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Affiliation(s)
- Laura H Jacobson
- The Florey Institute of Neuroscience and Mental Health, University of Melbourne, Victoria, Australia; Department of Pharmacology and Therapeutics, University of Melbourne, Victoria, Australia.
| | - Styliani Vlachou
- School of Nursing and Human Sciences, Faculty of Science and Health, Dublin City University, Glasnevin, Dublin
| | - David A Slattery
- Klinik für Psychiatrie, Psychosomatik und Psychotherapie, Universitätsklinikum Frankfurt, Frankfurt am Main, Germany
| | - Xia Li
- Department of Psychiatry, School of Medicine, University of California San Diego, La Jolla, California
| | - John F Cryan
- Department of Anatomy and Neuroscience, University College Cork, Cork, Ireland; Alimentary Pharmabiotic Centre, University College Cork, Cork, Ireland
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50
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Kakaei S, Khameneh ES. An efficient and simple ultrasound-assisted approach to synthesis of Baclofen. MAIN GROUP CHEMISTRY 2018. [DOI: 10.3233/mgc-180258] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Affiliation(s)
- Saeed Kakaei
- Material and Nuclear Fuel Research School, Nuclear Science and Technology Research Institute, Tehran, Iran
| | - Elham Sattarzadeh Khameneh
- Material and Nuclear Fuel Research School, Nuclear Science and Technology Research Institute, Tehran, Iran
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