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.

1 A study has been made of the pharmacology of the 5-hydroxytryptamine (5-HT)-induced depolarization responses that can be recorded extracellularly from the rat isolated cervical vagus nerve. 2 Phenylbiguanide (PBG) and 2-methyl-5-hydroxytryptamine (2-methyl-5-HT) were found to mimic the effects of 5-HT on the vagus nerve. Their ECjO values were respectively 2.0 fold and 3.9 fold greater than that of 5-HT. 3 Metoclopramide behaved as a reversible competitive antagonist of depolarization induced by PBG and 2-methyl-5-HT, with pKB values of 6.48 ± 0.04 and 6.64 ± 0.04, respectively. These agreed well with the pKB value of 6.60 ± 0.04 obtained previously for metoclopramide against 5-HT on the rat vagus nerve. 5-HT, PBG and 2-methyl-5-HT had no demonstrable agonist effects at non-5-HT receptors on the rat vagus nerve. 4 Tropacaine and m-chlorophenylpiperazine were found to behave as reversible competitive antagonists of 5-HT-induced depolarization of the vagus nerve. The pKB values were 6.29 ± 0.03 and 6.90 ± 0.03, respectively. 5 Quipazine, MDL 72222 and ICS 205-930 were also shown to be effective antagonists of 5-HT on the vagus nerve. However, although these compounds were highly potent, they all caused a marked concentration-dependent reduction in the amplitude of the maximum response to 5-HT. This behaviour was not consistent with a simple reversible competitive mechanism. 6 The results are discussed with reference to the current classification of mammalian peripheral neuronal 5-HT receptors.

The affinity of the non-peptide antagonist CP-96,345 for tachykinin NK1 receptors has been estimated in a range of species by use of both radioligand binding and functional assays. CP-96,345 was 30-120 fold less active at NK1 receptors in rat and mouse than in the other species examined, including man. These results demonstrate the existence of species variations in NK1 receptors.

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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.