New-generation 5-HT₄ receptor 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-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-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-HT ₄ receptor agonists and future drugs targeting organ-specific splice variants are promising approaches to treat GI dysmotility, particularly colonic diseases.