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The pharmacological properties of the novel selective 5‐HT 3 receptor antagonist, alosetron, and its effects on normal and perturbed small intestinal transit in the fasted rat
Author(s) -
Nick M. Clayton,
R Sargent,
A. Butler,
Jeremy D. Gale,
Miles Maxwell,
A. A. E. Hunt,
Vikki Barrett,
David Cambridge,
C Bountra,
P. P. A. Humphrey
Publication year - 1999
Publication title -
neurogastroenterology and motility
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.489
H-Index - 105
eISSN - 1365-2982
pISSN - 1350-1925
DOI - 10.1046/j.1365-2982.1999.00148.x
Subject(s) - medicine , agonist , pharmacology , receptor , antagonist , receptor antagonist , endocrinology , 5 ht receptor , vagus nerve , serotonin , stimulation
The purpose of this study was to investigate the pharmacological properties of the novel, selective 5‐HT 3 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‐HT 3 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 pK B 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 μg kg –1 , with an agonist dose ratio of approximately 3.0 at 1.0 μg 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‐HT 3 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.