Partial Agonism of 5-HT3 Receptors: A Novel Approach to the Symptomatic Treatmentof IBS-D

摘要

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 normalizebowel function without leading to a total block associated with severeconstipation. We have identified a new class of selective, orallyactive 5-HT3 receptor ligands with high 5-HT3 receptor affinity and low partial agonist activity currently inpreclinical development that should offer a significant advantageover existing therapies.