Continuous consumption combined with incomplete removal during wastewater treatment means residues of psychotropic drugs (PDs), including antidepressants, antipsychotics, antiepileptics and illicit drugs, are continuously entering the aquatic environment, where they have the potential to affect non-target organisms. Photochemical transformation is an important aspect to consider when evaluating the environmental persistence of PDs, particularly for those present in sunlit surface waters. This review summarizes the latest research on the photodegradation of typical PDs under environmentally relevant conditions. According to the analysis results, four classes of PDs discussed in this paper are influenced by direct and indirect photolysis. Indirect photodegradation has been more extensively studied for antidepressants and antiepileptics compared to antipsychotics and illicit drugs. Particularly, the photosensitization process of dissolved organic materials (DOM) in natural waters has received significant research attention due to its ubiquity and specificity. The direct photolysis pathway plays a less significant role, but it is still relevant for most PDs discussed in this paper. The photodegradation rates and pathways of PDs are influenced by various water constituents and parameters such as DOM, nitrate and pH value. The contradictory results reported in some studies can be attributed to differences in experimental conditions. Based on this analysis of the existing literature, the review also identifies several key aspects that warrant further research on PD photodegradation. These results and recommendations contribute to a better understanding of the environmental role of water matrixes and provide important new insights into the photochemical fate of PDs in aquatic environments.

For over seven decades, dopamine receptor 2 (D2 receptor) antagonists remained the mainstay treatment for neuropsychiatric disorders. Although it is effective for treating hyperdopaminergic symptoms, it is often ineffective for treating negative and cognitive deficits. Trace amine-associated receptor 1 (TAAR1) is a novel, pharmacological target in the treatment of schizophrenia and other neuropsychiatric conditions. Several TAAR1 agonists are currently being developed and are in various stages of clinical and preclinical development. Previous efforts to identify TAAR1 agonists have been hampered by challenges in pharmacological characterisation, the absence of experimentally determined structures, and species-specific preferences in ligand binding and recognition. Further, poor insights into the functional selectivity of the receptor led to the characterisation of ligands with analogous signalling mechanisms. Such approaches limited the understanding of divergent receptor signalling and their potential clinical utility. Recent cryogenic electron microscopic (cryo-EM) structures of human and mouse TAAR1 (hTAAR1 and mTAAR1, respectively) in complex with agonists and G proteins have revealed detailed atomic insights into the binding pockets, binding interactions and binding modes of several agonists including endogenous trace amines (β-phenylethylamine, 3-Iodothyronamine), psychostimulants (amphetamine, methamphetamine), clinical compounds (ulotaront, ralmitaront) and repurposed drugs (fenoldopam). The in vitro screening of drug libraries has also led to the discovery of novel TAAR1 agonists (asenapine, guanabenz, guanfacine) which can be used in clinical trials or further developed to treat different neuropsychiatric conditions. Furthermore, an understanding of unappreciated signalling mechanisms (Gq, Gs/Gq) by TAAR1 agonists has come to light with the discovery of selective compounds to treat schizophrenia-like phenotypes. In this review, we discuss the emergence of structure-based approaches in the discovery of novel TAAR1 agonists through drug repurposing strategies and structure-guided designs. Additionally, we discuss the functional selectivity of TAAR1 signalling, which provides important clues for developing disorder-specific compounds.

Trace amine-associated receptor 1 (TAAR1) is a G-protein-coupled receptor which is primarily expressed in the brain. It is activated by trace amines which play a role in regulating neurotransmitters like dopamine, serotonin and norepinephrine. TAAR1 agonists have potential applications in the treatment of neurological and psychiatric disorders, especially schizophrenia. In this study, we have used a structure-based virtual screening approach to identify potential TAAR1 agonist(s). We have modelled the structure of TAAR1 and predicted the binding pocket. Further, molecular docking of a few well-known antipsychotic drugs was carried out with TAAR1 model, which showed key interactions with the binding pocket. From screening a library of 5 million compounds from the Enamine REAL Database using structure-based virtual screening method, we shortlisted 12 compounds which showed good docking score, glide energy and interactions with the key residues. One lead compound (Z31378290) was finally selected. The lead compound showed promising binding affinity and stable interactions with TAAR1 during molecular dynamics simulations and demonstrated better van der Waals and binding energy than the known agonist, ulotaront. Our findings suggest that the lead compound may serve as a potential TAAR1 agonist, offering a promising avenue for the development of new therapies for neurological and psychiatric disorders.

Schizophrenia is a complex and severe mental illness. Current treatments for schizophrenia typically modulate dopaminergic neurotransmission by D₂-receptor blockade. While reducing positive symptoms of schizophrenia, current antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairments. For the last few decades, discovery efforts have sought nondopaminergic compounds with the aim to effectively treat the broad symptoms of schizophrenia. In this viewpoint, we provide an overview on trace-amine associated receptor-1 (TAAR1), which presents a clinically validated nondopaminergic target for treating schizophrenia and related disorders, with significantly less overall side-effect burden. TAAR1 agonists may also be specifically beneficial for the substance abuse comorbidity and metabolic syndrome that is often present in patients with schizophrenia.

Current medications for schizophrenia typically modulate dopaminergic neurotransmission. While affecting positive symptoms, antipsychotic drugs have little clinical effect on negative symptoms and cognitive impairment. Moreover, newer 'atypical' antipsychotic drugs also have significant metabolic adverse-effects. The recent positive clinical trial of the novel drug candidate SEP-363856, which targets non-dopamine receptors (trace amine-associated receptor and the 5HT_1A receptor), is a potentially promising development for the management of schizophrenia. In this perspective, we briefly overview the role of TAAR1 and the 5HT_1A receptor in schizophrenia and explore the specific binding characteristics of SEP-363856 at these receptors. Molecular dynamics simulations (MDS) indicate that SEP-363856 interacts with a small, common set of conserved residues within the TAAR1 and 5HT_1A ligand-binding domain. The primary interaction of SEP-363856 involves binding to the negatively charged aspartate residue (Asp103^3.32, TAAR1; Asp116^3.32, 5HT_1A). In general, the binding of SEP-363856 within TAAR1 involves a greater number of aromatic contacts compared to 5HT_1A. MDS provides important insights into the molecular basis of binding site interactions of SEP-363856 with TAAR1 and the 5HT_1A receptor, which will be beneficial for understanding the pharmacological uniqueness of SEP-363856 and for the design of novel drug candidates for these newly targeted receptors in the treatment of schizophrenia and related disorders.

The introduction of chlorpromazine and the work that ensued provided the foundation to reposition schizophrenia as a biological illness. The present paper follows the evolution of antipsychotics and their shift from 'typical' to 'atypical'. Atypicality is reviewed in reference to its original definition, clozapine's role, and developments that now leave the concept's utility in question. In a similar fashion, drug development is reviewed in the context of the illness' multiple symptom domains, as well as differences captured by clinical staging and phenotyping. Collectively, the evidence argues for a more nuanced approach to drug development that aligns with the illness' heterogeneity and complexity. Just as 'atypical' as a descriptor for antipsychotics may be outdated, it may be time to set aside the notion of developing drugs that treat 'schizophrenia'.

Dopamine (DA) and serotonin (5-HT) receptors are prime targets for the development of antipsychotics. The specific role of each receptor subtype to the pharmacological effects of antipsychotic drugs remains unclear. Understanding the relationship between antipsychotic drugs and their binding affinities at DA and 5-HT receptor subtypes is very important for antipsychotic drug discovery and could lead to new drugs with enhanced efficacies. We have previously disclosed SYA16263 (5) as an interesting compound with moderate radioligand binding affinity at the D₂ & D₃ receptors (Ki = 124 nM & 86 nM respectively) and high binding affinities towards D₄ and 5-HT_1A receptors (Ki = 3.5 nM & 1.1 nM respectively). Furthermore, we have demonstrated SYA16263 (5) is functionally selective and produces antipsychotic-like behavior but without inducing catalepsy in rats. Based on its pharmacological profile, we selected SYA16263 (5) to study its structure-affinity relationship with a view to obtaining new analogs that display receptor subtype selectivity. In this study, we present the synthesis of structurally modified SYA16263 (5) analogs and their receptor binding affinities at the DA and 5-HT receptor subtypes associated with antipsychotic action. Furthermore, we have identified compound 21 with no significant binding affinity at the D₂ receptor subtype but with moderate binding affinity at the D₃ and D₄ receptors subtypes. However, because 21 is able to demonstrate antipsychotic-like activity in a preliminary test, using the reversal of apomorphine-induced climbing behavior experiment in mice with SYA16263 and haloperidol as positive controls, we question the essential need of the D₂ receptor subtype in reversing apomorphine-induced climbing behavior.

There are nine subfamilies of TAARs. They are predominantly intracellular, located in the central nervous system and peripherally. They have a role in homeostasis and rheostasis, and also in olfaction. They demonstrate significant cross-talk with the monoamine system and are involved in the regulation of cAMP signalling and K⁺ channels. There is evidence to suggest that TAAR1 may be a promising therapeutic target for the treatment of schizophrenia, psychosis in Parkinson's disease, substance use disorders, and the metabolic syndrome and obesity. TAAR1 expression may also be a prognostic biomarker for cancers. A number of TAAR modulators have been identified, including endogenous ligands and new chemical entities. Some of these agents have shown efficacy in animal models of addiction behaviours, depression and anxiety. Only one agent, SEP-363856, has progressed to randomised clinical trials in humans; however further, larger studies with SEP-363856 are required to clarify its suitability as a new treatment for schizophrenia spectrum disorders. SEP-363856 is an agonist of TAAR1 and 5HT_1A and it is not clear to what extent its efficacy can be attributed to TAAR1 rather than to other drug targets. However, current research suggests that TAAR1 has an important role in human physiology and pathophysiology. TAAR1 modulators may become an important new drug class for the management of a wide array of mental disorders in the future.