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.

N M Clayton, R Sargent, A Butler, J Gale, M P Maxwell, A A Hunt, V J Barrett, D Cambridge, C Bountra, P P Humphrey

GlaxoWellcome, Stevenage, Herts., UK. nc0537@ggr.co.uk

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society 1999 Jun

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The purpose of this study was to investigate the pharmacological properties of the novel, selective 5-HT3 receptor antagonist, alosetron, and its effects 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 values of 9.8 (n = 3) and 9.4 (n = 6), respectively. In selectivity studies alosetron had little or no significant affinity for any of the many other receptors and ion channels studied. Alosetron potently antagonized the depolarization produced by 5-HT in the rat vagus nerve (estimated pKB value of 9.8, n = 25). In anaesthetized rats, i. v. administration of alosetron inhibited 2-methyl-5-HT induced bradycardia (Bezold Jarisch index) at 1 and 3 microg kg-1, with an agonist dose ratio of approximately 3.0 at 1.0 microg 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 significant effect on normal small intestinal propulsion in the rat, but fully reversed the increase in intestinal propulsion (96%, n = 3) produced by egg albumin challenge. Alosetron is a highly selective 5-HT3 antagonist which normalizes perturbed small intestinal propulsion. Previous clinical data in IBS patients together with the transit data provide a good rationale for further studies with alosetron in IBS patients.

Citation

N M Clayton, R Sargent, A Butler, J Gale, M P Maxwell, A A Hunt, V J Barrett, D Cambridge, C Bountra, P P Humphrey. 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. Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society. 1999 Jun;11(3):207-17