1 This paper describes the pharmacology of the novel 5-hydroxytryptamine3 (5-HT3) receptor antagonist GR38032F. 2 On the isolated vagus nerve and superior cervical ganglion of the rat, R,S-GR38032F behaved as a reversible competitive antagonist of 5-HT-induced depolarization with pKB values of 8.61 + 0.08 (n = 19) and 8.13 + 0.07 (n = 16), respectively. The resolved R-and S-isomers of GR38032F were approximately equipotent as 5-HT antagonists on the rat vagus nerve: the pKB values were 8.95 + 0.05 (n = 16) and 8.63 + 0.08 (n = 17), respectively. R,S-GR38032F was also an effective antagonist of 5-HT on the rabbit isolated vagus nerve: in this case the pKB value was 9.40 + 0.14 (n = 4).3 On the rabbit isolated heart, low concentrations of R,S-GR38032F (3 x 10-1`4l x 10-9M)antagonized the positive chronotropic effect of 5-HT and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT). However, the effects of the compound did not appear consistent with simple reversible competition. 4 On the longitudinal smooth muscle of the guinea-pig ileum, RS-GR38032F caused concentration-dependent parallel rightward displacement of the 2-methyl-5-HT concentrationcontraction response curve; in contrast, a portion of the response to 5-HT appeared resistant to R,S-GR38032F. pKB values estimated from the effects of the compound against 2-methyl-5-HT or the inhibitable portion of the response to 5-HT were 7.31 + 0.06 (n = 8) and 7.33 + 0.13 (n = 8), respectively. Against 2-methyl-5-HT, R-GR38032F seemed more potent (pKB 7.20 + 0.10; n = 6) than S-GR38032F (pKB 6.30 + 0.05; n = 6).5 R,S-GR38032F is highly selective for 5-HT3 receptors, and at concentrations of 3 x 10-6_ 3 x 10-M, had negligible agonist or antagonist activity on other 5-HT or non-5-HT receptorcontaining tissues on which it was tested. 6 The potency and duration of action of R,S-GR38032F in blocking 5-HT3 receptors in vivo were assessed by measuring its ability to antagonize the bradycardic response to 5-HT or 2-methyl-5-HT administered intravenously (i.v.) to anaesthetized animals. For i.v. administration to the rat, the ED50 for R,S-GR38032F against 2-methyl-5-HT (100pgkg-1) was 0.4 (95% confidence limits 0.18-0.87) ygkg-1 (n = 10); the corresponding value for oral administration to this species was 7.0 (3.0-22.0)pgkg-' (n = 8-10 per dose level). R,S-GR38032F was similarly effective in the anaesthetized cat. 7 The present results are discussed with reference to the postulated existence of subtypes of the 5-HT3 receptor.

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The pharmacological characterization of the 5‐HT3 receptors in guinea‐pig isolated tissues is described. The tissues used were ileum (longitudinal muscle‐myenteric plexus), colon and vagus nerve. The guinea‐pig isolated colon is a novel preparation. In the guinea‐pig isolated ileum, 5‐hydroxytryptamine (5‐HT, 1 × 10−8−3 × 10−5 m) and the selective 5‐HT3 receptor agonist 2‐methyl‐5‐HT (3 × 10−7−1 × 10−4 m) caused concentration‐related contractions. The 5‐HT concentration‐response curve was biphasic whilst the 2‐methyl‐5‐HT curve was monophasic. The EC50 value for the low potency portion of the 5‐HT curve was 4.1 × 10−6 m. The EC50 for 2‐methyl‐5‐HT was 1.23 × 10−5 m. Selective 5‐HT3 receptor antagonists caused rightward shifts of the 2‐methyl‐5‐HT curve and the lower potency portion of the 5‐HT curve. Neither ketanserin (1 × 10−6 m) nor methysergide (1 × 10−5 m) antagonized the responses to 5‐HT or 2‐methyl‐5‐HT. In the guinea‐pig isolated colon, 5‐HT (3 × 10−7−3 × 10−5 m; EC50 2.4 × 10−6 m) caused contractions which were mimicked by 2‐methyl‐5‐HT (1 × 10−6−1 × 10−4 m; EC50 7.2 × 10−6 m). Selective 5‐HT3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Neither ketanserin (1 × 10−6 m) nor methysergide (1 × 10−5 m) had any effect on responses to 5‐HT or 2‐methyl‐5‐HT. In the guinea‐pig isolated vagus nerve, 5‐HT (1 × 10−6−3 × 10−4 m) and 2‐methyl‐5‐HT (1 × 10−5−1 × 10−3 m; EC50 7.6 × 10−5 m) caused depolarizations; at higher concentrations there were afterhyperpolarizations. The maximum response to 2‐methyl‐5‐HT was less than half that to 5‐HT. Selective 5‐HT3 receptor antagonists caused rightward displacements of the 5‐HT concentration‐response curves. Antagonists at other 5‐HT receptors (ketanserin, 1 × 10−5 m and methysergide, 1 × 10−6 m) had no effect. The estimated affinity values of 5‐HT3 receptor antagonists correlated well between the three models. Phenylbiguanide was inactive as an agonist or antagonist (up to 1 × 10−4 m) in each preparation. Comparisons with antagonist affinity values obtained in the rat isolated vagus nerve revealed marked differences. Antagonists were generally more potent on the rat isolated vagus nerve, although the differences varied considerably between antagonists. The results are discussed in terms of species‐related receptor differences.

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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.