Pharmacological activity of the isomers of LY53857, potent and selective 5-HT2 receptor antagonists.

LY53857 is an ergoline derivative that is a potent and selective antagonist at 5-HT2 receptors. The present study investigated the activities of the diastereomers of LY53857. The SS- and RR-isomers and the meso mixture of isomers of LY53857 all showed affinity for 5-HT2 receptors approximately 100-fold higher than for 5-HT1 receptors based on radiolabeled ligand binding studies in rat cortical membranes. Based on these binding data, the meso mixture of isomers was one-half as potent as the other two isomers. Consistent with the binding data, the SS- and RR-isomers and the meso mixture of isomers all showed high affinity as antagonists of 5-HT2 receptors in the rat jugular vein, with the meso mixture of isomers being slightly less potent than the other two isomers. Affinity of the isomers at alpha-1 and alpha-2 receptors was low. Approximately 100,000- and 2000-fold higher concentrations were required for antagonism of alpha-1 and alpha-2 receptors, respectively, relative to 5-HT2 receptors. A similar profile of selectivity was demonstrated for each of the isomers studied. These in vitro data were consistent with in vivo data showing the high i.v. and p.o. potency of all the isomers to antagonize the pressor response to i.v. administration of serotonin in pithed spontaneously hypertensive rats. As seen in vitro, the meso mixture of isomers was slightly less potent than the SS- and RR-isomers after p.o. administration in vivo.(ABSTRACT TRUNCATED AT 250 WORDS)