The pharmacological properties of the novel selective 5-HT3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat

The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effe cts on transit time in both the normal and perturbed small intestine of the rat. Alosetron concentration-dependently inhibited radioligand binding in membranes containing rat and human 5-HT3 receptors with estimated pKi value s of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alos etron had little or no significant affinity for any of the many other recep tors and ion channels studied. Alosetron potently antagonized the depolariz ation produced by 5-HT in the rat vagus nerve (estimated pK(B) value of 9.8 , n = 25). In anaesthetized rats, i.v. administration of alosetron inhibite d 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 mu g kg(-1), with an agonist dose ratio of approximately 3.0 at 1.0 mu g kg(-1), = 3-5). Alosetron administered via the duodenum also inhibited this reflex , with duration of action that was significantly longer than that seen with ondansetron (120-60 min, respectively, n = 6). Alosetron had no significan t effect on normal small intestinal propulsion in the rat, but fully revers ed the increase in intestinal propulsion (96%, n = 3) produced by egg album in challenge. Alosetron is a highly selective 5-HT3 antagonist which normal izes perturbed small intestinal propulsion. Previous clinical data in IBS p atients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.