Abstract

Background: 5-HT₄ receptor plays important roles regulating gastrointestinal motility, enteric neuronal signaling and visceral pain in the gastrointestinal tract. Over the past decade, the 5-HT₄ receptor has been highlighted as an attractive drug target for the treatment of gastrointestinal motility disorders such as irritable bowel syndrome, chronic constipation, functional dyspepsia, gastroparesis and so on. Objectives: This article aims to provide an overview of serotonin receptors related to the gastrointestinal motility disorders, and to address the characteristics of past, current and future 5-HT₄ receptor agonists for treatment of functional gastrointestinal disorders, focusing on the pharmacology, efficacy and safety profile.

Methods: A literature search was performed using databases including MEDLINE (1974-July 2014), SCOPUS, Google Scholar, abstracts presented at the gastroenterology meetings and unpublished data from pharmaceutical companies. Specific search terms used were “5-HT₄ receptor agonist”, “gastrointestinal motility disorder”, “irritable bowel syndrome” and “chronic constipation”.

Conclusion: In contrast to nonselective 5-HT₄ receptor agonists such as tegaserod and cisapride, which were withdrawn due to cardiovascular adverse effects, several potent and selective 5-HT₄ receptor agonists have been found to display the improved safety profile and the therapeutic potential in clinical trials and preclinical studies. These include agents such as prucalopride, velusetrag, naronapride, YKP10811 and DA-6886. These compounds differ in chemistry, efficacy, adverse effects and pharmacokinetics. The various properties of 5-HT₄ receptor agonists will help us not only to enable adequate treatment to be tailored to the needs of each patient but also to stimulate further efforts to develop promising innovative drugs for gastrointestinal motility disorders.