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


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
Manabe
Noriaki
N
Clinical Enteric Neuroscience Translational and Epidemiological Research (CENTER), Mayo Clinic, Rochester, MN 55905, USA.
Wong
Banny S
BS
Camilleri
Michael
M
D000818:Animals; D002986:Clinical Trials as Topic; D003109:Colonic Diseases, Functional / Q000188:drug therapy / Q000503:physiopathology; D016503:Drug Delivery Systems; D005765:Gastrointestinal Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D005767:Gastrointestinal Diseases / Q000188:drug therapy / Q000503:physiopathology; D005769:Gastrointestinal Motility / Q000187:drug effects*; D006801:Humans; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*
D005765:Gastrointestinal Agents; D058828:Serotonin 5-HT4 Receptor Agonists; D017366:Serotonin Receptor Agonists