Antagonistic properties of McNeil‐A‐343 at 5‐HT 4 and 5‐HT 3 receptors

1 This study describes the in vitro interaction of the muscarinic ligand McNeil‐A‐343 with two 5‐hydroxytryptamine (5‐HT) receptor subtypes, the 5‐HT 4 and 5‐HT 3 receptors, using functional as well as radioligand binding studies. 2 In the rat oesophageal muscularis mucosae, precontracted with carbachol, McNeil‐A‐343 was a competitive antagonist (pA 2 6.2) of the 5‐HT 4 receptor which mediates the relaxation induced by 5‐HT. The compound per se relaxed the oesophagus at high concentration only (≥ 10 μ m ), an effect unchanged by desensitization of the 5‐HT 4 receptor with 10 μ m 5‐methoxytryptamine. In the same preparation in the absence of tone, McNeil‐A‐343 displaced the carbachol concentration‐response curve to the right, yielding an apparent affinity (pA 2 ) of 4.9 for muscarinic receptors. 3 In the rat isolated superior cervical ganglion preparation, after blockade of muscarinic and nicotinic receptors, McNeil‐A‐343 caused a concentration‐dependent depolarization that was unaffected by 100 n m ondansetron. The concentration‐fast depolarization curve to 5‐HT, mediated by the 5‐HT 3 receptor, was displaced to the right by McNeil‐A‐343, which showed an apparent affinity (pA 2 ) of 4.8 for the 5‐HT 3 subtype. 4 In binding studies, McNeil‐A‐343 recognized a single population of 5‐HT 4 receptors in pig caudate nucleus, with a pAi of 5.9. The binding affinity of McNeil‐A‐343 for 5‐HT 3 receptors in NG 108‐15 cells was approximately four times lower (p K 1 5.3). Binding affinities ( p K 1 ) for muscarinic receptor subtypes in rat tissues were 5.3 (M b cortex), 5.2 (M 2 , heart) and 4.9 (M 3 , submandibular glands), respectively. 5 McNeil‐A‐343 is an antagonist at 5‐HT 4 and 5‐HT 3 receptors; the interaction of the compound with these receptor subtypes (notably the 5‐HT 4 ) occurs in a range of concentrations which generally overlaps that relevant to the interaction with muscarinic receptors.