The 5-HT4 receptor agonist, tegaserod, is a potent 5-HT2B receptor antagonist in vitro and in vivo


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  • Tegaserod (Zelnorm®) is a potent 5-hydroxytryptamine4 (5-HT4) receptor agonist with clinical efficacy in disorders associated with reduced gastrointestinal motility and transit. The present study investigated the interaction of tegaserod with 5-HT2 receptors, and compared its potency in this respect to its 5-HT4 receptor agonist activity.

  • Tegaserod had significant binding affinity for human recombinant 5-HT2A, 5-HT2B and 5-HT2C receptors (pKi=7.5, 8.4 and 7.0, respectively). The 5-HT2B receptor-binding affinity of tegaserod was identical to that at human recombinant 5-HT4(c) receptors (mean pKi=8.4) in human embryonic kidney-293 (HEK-293) cells stably transfected with the human 5-HT4(c) receptor.

  • Tegaserod (0.1–3 μM) inhibited 5-HT-mediated contraction of the rat isolated stomach fundus potently (pA2=8.3), consistent with 5-HT2B 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-HT4(c) receptor (mean pEC50=8.6), as well as 5-HT4 receptor-mediated relaxation of the rat isolated oesophagus (mean pEC50=8.2) and contraction of the guinea-pig isolated colon (mean pEC50=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-HT2B receptor agonists. At similar doses, tegaserod (1 and 3 mg kg−1 subcutaneously) evoked a 5-HT4 receptor-mediated increase in colonic transit in conscious guinea-pigs.

  • The data from this study indicate that tegaserod antagonizes 5-HT2B receptors at concentrations similar to those that activate 5-HT4 receptors. It remains to be determined whether this 5-HT2B receptor antagonist activity of tegaserod contributes to its clinical profile.

British Journal of Pharmacology (2004) 143, 549–560. doi:10.1038/sj.bjp.0705929