Pharmacological characterization of tegaserod at the wild type and 124Cys variant of the human 5-HT1B receptor

Abstract

Sumatriptan, an antimigraine drug, causes contraction of human coronary arteries through activation of 5-HT1B receptors which couple to Gi/Go inducing inhibition of adenylate cyclase. At a rare, naturally occurring human receptor variant (124Cys-h5-HT1B), sumatriptan has previously been shown to act as a more potent agonist than at wild-type receptor. Tegaserod, a 5-HT4-receptor agonist, developed for the treatment of functional gastrointestinal disorders, has been suspected to be involved in very rare cardiac ischemic events in patients with cardiovascular risk factors. In this study, we examined the potential agonist-like effects of tegaserod in comparison with sumatriptan at heterologously expressed human wild type and 124Cys-variant 5-HT1B receptors, using assays addressing G-protein coupling and inhibition of forskolin-stimulated cyclic AMP accumulation. Sumatriptan exhibited agonist effects as previously reported, whereas tegaserod acted as partial agonist at both wild type and 124Cys-variant h5-HT1B receptors (expressed in rat C6 glioma cells). Sumatriptan and tegaserod were more potent at the 124Cys-variant h5-HT1B receptor. It remains to be shown whether the very rare cardiovascular side effects reported with these drugs are predominantly observed in patients homozygously expressing the variant receptor.