Partial agonism of 5-HT3 receptors: a novel approach to the symptomatic treatment of IBS-D.
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.
Albany Molecular Research Inc., 26 Corporate Circle, Albany, New York 12212, United States. Nicholas.Moore@amriglobal.com
Nicholas A
NA
Moore
Bruce J
BJ
Sargent
David D
DD
Manning
Peter R
PR
Guzzo
D006801:Humans; D043183:Irritable Bowel Syndrome / Q000188:drug therapy*; D058446:Ligand-Gated Ion Channels / Q000187:drug effects; D044406:Receptors, Serotonin, 5-HT3 / Q000502:physiology; D058827:Serotonin 5-HT3 Receptor Agonists / Q000494:pharmacology / Q000627:therapeutic use*; D058831:Serotonin 5-HT3 Receptor Antagonists / Q000494:pharmacology / Q000627:therapeutic use
D058446:Ligand-Gated Ion Channels; D044406:Receptors, Serotonin, 5-HT3; D058827:Serotonin 5-HT3 Receptor Agonists; D058831:Serotonin 5-HT3 Receptor Antagonists