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

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• 作者：Nicholas A. Moore ; Bruce J. Sargent ; David D. Manning ; Peter R. Guzzo
• 刊名：ACS Chemical Neuroscience
• 出版年：2013
• 出版时间：January 16, 2013
• 年：2013
• 卷：4
• 期：1
• 页码：43-47
• 全文大小：230K
• 年卷期：v.4,no.1(January 16, 2013)
• ISSN：1948-7193

文摘

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鈥?0% 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.

Keywords:

5-HT₃ receptor; partial agonist; irritable bowel syndrome; IBS