New-generation 5-HT4receptor agonists: potential for treatment of gastrointestinal motility disorders

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-hydroxytryptamine4 (5-HT4) receptors are targets for the treatment of GI motility disorders. However, older 5-HT4 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-HT4, 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-HT4 receptor agonists.What the reader will gain: Prucalopride, ATI-7505, and velusetrag (TD-5108) are highly selective, high-affinity 5-HT4 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-HT4 receptor agonists have safe cardiac profiles.Take home message: New-generation 5-HT4 receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.