Constipation, IBS and the 5-HT4 Receptor: What Role for Prucalopride?

After the problems associated with the non-selective 5-HT4 receptor agonists cisapride and tegaserod, the 5-HT4 receptor is now beginning to come in from the cold. Thus, prucalopride is now the first of a new class of drug defined by selectivity and high intrinsic activity at the 5-HT4 receptor. Prucalopride has been developed for treatment of chronic constipation rather than constipation-predominant irritable bowel syndrome (IBS). This follows the trend of first evaluating new gastrointestinal (GI) prokinetic drugs in disorders where disrupted GI motility is known to exist, rather than in a functional bowel disorder where changes in motility are uncertain. If prucalopride is not progressed towards the IBS indication, it has at least shown the way for other selective 5-HT4 receptor agonists. Most notable among these is TD-5108 (velusetrag), also characterized by good selectivity at the 5-HT4 receptor, high intrinsic activity and efficacy in patients with chronic constipation.