Evolving prokinetic therapy: New targets and therapeutic opportunities in gastrointestinal motility disorders

doi:10.4292/wjgpt.v17.i2.118616

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World Journal of Gastrointestinal Pharmacology and Therapeutics

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2150-5349

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Baishideng Publishing Group Inc, 7041 Koll Center Parkway, Suite 160, Pleasanton, CA 94566, USA

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Copyright: ©Author(s) 2026. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution-NonCommercial (CC BY-NC 4.0) license. No commercial re-use. See permissions. Published by Baishideng Publishing Group Inc.

World J Gastrointest Pharmacol Ther. Jun 5, 2026; 17(2): 118616
Published online Jun 5, 2026. doi: 10.4292/wjgpt.v17.i2.118616

Evolving prokinetic therapy: New targets and therapeutic opportunities in gastrointestinal motility disorders

Omesh Goyal, Rishi Chowdhary, Tanisha Sehgal, Tanvi Joshi, Akshit Bhambri, Insiya Mohammed Rampurawala, Gurmanleen Singh Sohi, Arghadip Das, Kirti Arora, Ashita Rukmini Vuthaluru, Manjeet Kumar Goyal

Omesh Goyal, Department of Gastroenterology, Dayanand Medical College and Hospital, Tagore Nagar, Ludhiana 141001, Punjab, India

Rishi Chowdhary, Department of Medicine, MetroHealth Medical Center, Cleveland, OH 44109, United States

Tanisha Sehgal, Department of Internal Medicine, Dayanand Medical College and Hospital, Ludhiana 141001, Punjab, India

Tanvi Joshi, Department of Internal Medicine, Shrimati Kashibai Navale Medical College and General Hospital, Pune 411041, Mahārāshtra, India

Akshit Bhambri, Department of Internal Medicine, Esic Medical College and Hospital, Hyderabad, Hyderabad 500038, Telangāna, India

Insiya Mohammed Rampurawala, Department of Internal Medicine, J.S.S Medical College, JSS Academy of Higher Education and Research, Mysuru 570015, India

Gurmanleen Singh Sohi, Department of Internal Medicine, Public Medical College, Patiala 147001, India

Arghadip Das, Department of Internal Medicine, Nilratan Sircar Medical College and Hospital, Kolkata 700014, India

Kirti Arora, Department of Internal Medicine, Cleveland Clinic Akron General, Akron, Ohio 44307, United States

Ashita Rukmini Vuthaluru, Department of Anesthesiology, All India Institute of Medical Sciences, New Delhi 110029, Delhi, India

Manjeet Kumar Goyal, Department of Internal Medicine, Cleveland Clinic Akron General Hospital, Akron, OH 44308, United States

Co-first authors: Omesh Goyal and Rishi Chowdhary.

Co-corresponding authors: Ashita Rukmini Vuthaluru and Manjeet Kumar Goyal.

Author contributions: Chowdhary R and Goyal MK conceived the study idea and were responsible for the overall study design and strategic direction of the manuscript; Chowdhary R, Goyal O, and Sehgal T conducted an extensive literature search and were involved in the identification, selection, and appraisal of relevant studies; Joshi T, Bhambari A, and Rampurwala IM contributed to systematic data extraction, organization of evidence, and synthesis of key findings across thematic areas; Das A and Soni GS played a major role in drafting the initial versions of the manuscript, including core sections and supporting tables and figures; Arora K and Vuthaluru AR contributed to manuscript structuring, language refinement, formatting according to journal requirements, and critical revision to improve clarity and coherence; Goyal O and Chowdhary R have made crucial and indispensable contributions towards the completion of the project and thus qualified as the co-first authors of the paper; Vuthaluru AR and Goyal MK have played important and indispensable roles in the manuscript preparation as the co-corresponding authors, while Goyal MK oversaw the entire project, provided senior supervision, and critically reviewed the manuscript for important intellectual content; all authors contributed to manuscript revision, approved the final version for submission, and agree to be accountable for the accuracy and integrity of the work.

AI contribution statement: Grammarly (as it is built into MS Word) was used for minor language editing and grammar correction. All sections were independently conceptualised, written, and revised by the authors. AI tools were used solely for basic grammar correction and improving language clarity. They were not used for data analysis, content generation, or substantive writing. AI tools had no role in the study design, data interpretation, or formulation of conclusions. No images in the manuscript were generated using AI tools.

Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.

Corresponding author: Manjeet Kumar Goyal, Department of Internal Medicine, Cleveland Clinic Akron General Hospital, 1 Akron General Avenue, Akron, OH 44308, United States. manjeetgoyal@gmail.com

Received: January 7, 2026
Revised: January 30, 2026
Accepted: March 4, 2026
Published online: June 5, 2026
Processing time: 140 Days and 19 Hours

Abstract

Gastroparesis, functional dyspepsia, chronic constipation, esophageal motility disorders, and colonic dysmotility are among the gastrointestinal (GI) motility disorders that constitute a significant global health burden. These disorders lead to reduced quality of life, higher healthcare utilization, and substantial socioeconomic costs. Therapeutic options are still scarce despite their prevalence. Prokinetic medications currently on the market offer only modest symptomatic relief, frequently reaching a plateau in efficacy, and their long-term use is limited by safety concerns, especially those related to cardiovascular and neurological side effects, as well as limited regional availability of some agents. The conceptual framework has moved beyond a purely neurocentric model due to recent advances in our understanding of GI motor physiology. The integrated functions of enteric neurobiology, gut-brain axis signaling, smooth muscle contractile pathways, interstitial cells of Cajal as motility pacemakers, and neuromodulatory circuits are highlighted by emerging mechanistic insights. These advancements have made it easier to find new pharmacologic targets and treatment approaches. An overview of new classes of prokinetic and motility-modulating drugs, such as selective receptor agonists and antagonists, hormone-based treatments, neuromodulators, and drugs that target pacemaker cell and smooth muscle function, is given in this review. Lastly, the clinical ramifications of these developing treatments are examined, with a focus on individualized treatment plans and potential future paths to enhance GI motility disorder efficacy, safety, and disease-specific management.

Keywords: Gastrointestinal motility disorders; Prokinetic agents; Gastroparesis; Dyspepsia; Constipation; Disorders of gut brain interaction; Functional gastrointestinal disorders; Enteric nervous system; Serotonin receptor agonists; Dopamine antagonists; Ghrelin

Core Tip: Prokinetic therapy has long been constrained by modest efficacy, tachyphylaxis, and significant cardiovascular and neurological safety concerns, limiting sustained clinical benefit in gastrointestinal motility disorders. This review redefines prokinetic treatment through an integrated pathophysiological framework that extends beyond traditional neuro-centric models to encompass enteric neurobiology, smooth muscle signalling, interstitial cells of Cajal, gut-brain axis modulation, and hormonal regulation. Emerging agents such as selective 5-hydroxytryptamine type 4 agonists, motilin and ghrelin receptor agonists, sodium/hydrogen exchanger-3 inhibitors, and neuromodulatory approaches, which offer improved mechanistic precision and safety. A phenotype-driven, precision-medicine strategy is essential to optimize therapeutic outcomes and guide future drug development in motility disorders.