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

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Abstract
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

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