Partial Agonism of 5‑HT3 Receptors: A Novel Approach to the Symptomatic Treatment of IBS‑D

• Published in: ACS chemical neuroscience Vol. 4; no. 1; pp. 43 - 47
• Main Authors: Moore, Nicholas A, Sargent, Bruce J, Manning, David D, Guzzo, Peter R
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 16.01.2013
• Subjects: Humans; Irritable Bowel Syndrome - drug therapy; Ligand-Gated Ion Channels - drug effects; Receptors, Serotonin, 5-HT3 - physiology; Review; Serotonin 5-HT3 Receptor Agonists - pharmacology; Serotonin 5-HT3 Receptor Agonists - therapeutic use; Serotonin 5-HT3 Receptor Antagonists - pharmacology; Serotonin 5-HT3 Receptor Antagonists - therapeutic use; partial agonist; IBS; irritable bowel syndrome; 5-HT3 receptor
• ISSN: 1948-7193; 1948-7193
• DOI: 10.1021/cn300166c

Irritable bowel syndrome (IBS) is a functional bowel disorder characterized by abdominal pain, discomfort, and altered bowel habits, which have a significant impact on quality of life for approximately 10–20% of the population. IBS can be divided into three main types IBS-D (diarrhea predominant), IBS-C (constipation predominant), and mixed or alternating IBS. 5-HT3 receptor antagonism has proved to be an efficacious treatment option for IBS-D. For example, alosetron displays efficacy in the treatment of multiple symptoms, including abdominal pain, discomfort, urgency, stool frequency and consistency. However, significant constipation occurred in approximately 25% of patients, leading to withdrawal of up to 10% of patients in clinical trials. Targeting compounds with partial agonist activity at the 5-HT3 receptor represents a mechanistic departure from the classic 5-HT3 receptor antagonist approach and should result in agents that are applicable to a broader array of IBS patient populations. Attenuation of the activity of the ion channel without completely abolishing its function may control or normalize bowel function without leading to a total block associated with severe constipation. We have identified a new class of selective, orally active 5-HT3 receptor ligands with high 5-HT3 receptor affinity and low partial agonist activity currently in preclinical development that should offer a significant advantage over existing therapies.