The 5‐HT 4 receptor agonist, tegaserod, is a potent 5‐HT 2B receptor antagonist in vitro and in vivo

Tegaserod (Zelnorm®) is a potent 5‐hydroxytryptamine 4 (5‐HT 4 ) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5‐HT 2 receptors, and compared its potency in this respect to its 5‐HT 4 receptor agonist activity. Tegaserod had significant binding affinity for human recombinant 5‐HT 2A , 5‐HT 2B and 5‐HT 2C receptors (p K i =7.5, 8.4 and 7.0, respectively). The 5‐HT 2B receptor‐binding affinity of tegaserod was identical to that at human recombinant 5‐HT 4(c) receptors (mean p K i =8.4) in human embryonic kidney‐293 (HEK‐293) cells stably transfected with the human 5‐HT 4(c) receptor. Tegaserod (0.1–3 μ M ) inhibited 5‐HT‐mediated contraction of the rat isolated stomach fundus potently (p A 2 =8.3), consistent with 5‐HT 2B receptor antagonist activity. Tegaserod produced, with similar potency, an elevation of adenosine 3′,5′ cyclic monophosphate in HEK‐293 cells stably transfected with the human 5‐HT 4(c) receptor (mean pEC 50 =8.6), as well as 5‐HT 4 receptor‐mediated relaxation of the rat isolated oesophagus (mean pEC 50 =8.2) and contraction of the guinea‐pig isolated colon (mean pEC 50 =8.3). Following subcutaneous administration, tegaserod (0.3 or 1 mg kg −1 ) inhibited contractions of the stomach fundus in anaesthetized rats in response to intravenous dosing of α ‐methyl 5‐HT (0.03 mg kg −1 ) and BW 723C86 (0.3 mg kg −1 ), selective 5‐HT 2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg −1 subcutaneously) evoked a 5‐HT 4 receptor‐mediated increase in colonic transit in conscious guinea‐pigs. The data from this study indicate that tegaserod antagonizes 5‐HT 2B receptors at concentrations similar to those that activate 5‐HT 4 receptors. It remains to be determined whether this 5‐HT 2B receptor antagonist activity of tegaserod contributes to its clinical profile. British Journal of Pharmacology (2004) 143 , 549–560. doi: 10.1038/sj.bjp.0705929