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Partial agonism of 5-HT3 receptors: a novel approach to the symptomatic treatment of IBS-D.

Abstract
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-HT(3) 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-HT(3) receptor represents a mechanistic departure from the classic 5-HT(3) 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-HT(3) receptor ligands with high 5-HT(3) receptor affinity and low partial agonist activity currently in preclinical development that should offer a significant advantage over existing therapies.
AuthorsNicholas A Moore, Bruce J Sargent, David D Manning, Peter R Guzzo
JournalACS chemical neuroscience (ACS Chem Neurosci) Vol. 4 Issue 1 Pg. 43-7 (Jan 16 2013) ISSN: 1948-7193 [Electronic] United States
PMID23342199 (Publication Type: Journal Article, Review)
Chemical References
  • Ligand-Gated Ion Channels
  • Receptors, Serotonin, 5-HT3
  • Serotonin 5-HT3 Receptor Agonists
  • Serotonin 5-HT3 Receptor Antagonists
Topics
  • Humans
  • Irritable Bowel Syndrome (drug therapy)
  • Ligand-Gated Ion Channels (drug effects)
  • Receptors, Serotonin, 5-HT3 (physiology)
  • Serotonin 5-HT3 Receptor Agonists (pharmacology, therapeutic use)
  • Serotonin 5-HT3 Receptor Antagonists (pharmacology, therapeutic use)

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