New-generation 5-HT4 receptor agonists: potential for treatment of gastrointestinal motility disorders.

Abstract

IMPORTANCE OF THE FIELD:

Gastrointestinal (GI) dysmotility is an important mechanism in functional GI disorders (FGIDs) including constipation, irritable bowel syndrome, functional dyspepsia, and gastroparesis. 5-hydroxytryptamine(4) (5-HT(4)) receptors are targets for the treatment of GI motility disorders. However, older 5-HT(4) receptor agonists had limited clinical success because they were associated with changes in the function of the cardiac HERG potassium channel.

AREAS COVERED IN THIS REVIEW:

We conducted a PubMed search using the following key words alone or in combination: 5-HT(4), safety, toxicity, pharmacokinetics, pharmacodynamics, clinical trial, cardiac, hERG, arrhythmia, potassium current, elderly, prucalopride, ATI-7505, and velusetrag (TD-5108), to review mechanisms of action, clinical efficacy, safety and tolerability of three new-generation 5-HT(4) receptor agonists.

WHAT THE READER WILL GAIN:

Prucalopride, ATI-7505, and velusetrag (TD-5108) are highly selective, high-affinity 5-HT(4) receptor agonists that are devoid of action on other receptors within their therapeutic range. Their efficacy has been demonstrated in pharmacodynamic studies which demonstrate acceleration of colonic transit and, to a variable degree, in clinical trials that significantly relieve chronic constipation. Currently available evidence shows that the new 5-HT(4) receptor agonists have safe cardiac profiles.

TAKE HOME MESSAGE:

New-generation 5-HT(4) receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.

• Authors: Noriaki Manabe, Banny S Wong, Michael Camilleri
• Journal: Expert opinion on investigational drugs (Expert Opin Investig Drugs) Vol. 19 Issue 6 Pg. 765-75 (Jun 2010) ISSN: 1744-7658 [Electronic] England
• PMID: 20408739 (Publication Type: Journal Article, Review)

Chemical References

• Gastrointestinal Agents
• Serotonin 5-HT4 Receptor Agonists
• Serotonin Receptor Agonists

Topics

• Animals
• Clinical Trials as Topic
• Colonic Diseases, Functional (drug therapy, physiopathology)
• Drug Delivery Systems
• Gastrointestinal Agents (adverse effects, pharmacology, therapeutic use)
• Gastrointestinal Diseases (drug therapy, physiopathology)
• Gastrointestinal Motility (drug effects)
• Humans
• Serotonin 5-HT4 Receptor Agonists
• Serotonin Receptor Agonists (adverse effects, pharmacology, therapeutic use)