PHARMACOLOGICAL ACTIVITY OF THE ISOMERS OF LY53857, POTENT AND SELECTIVE 5-HT2 RECEPTOR ANTAGONISTS

  • 1 January 1985
    • journal article
    • research article
    • Vol. 235  (2) , 319-323
Abstract
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. The SS- and RR-isomers and the meso mixture of isomers were likewise found to antagonize potently central serotonin receptors based on inhibition of quipazine-induced elevations in serum corticosterone. Once again, the meso mixture of isomers was approximately one-half as potent as the RR- or SS-isomers in inhibiting central serotonin receptors. Based on the similar potency and selectivity of the isomers of LY53857, these studies indicate that the stereochemical configuration of the ester side chain in LY53857 is not crucial for binding to the 5-HT2 receptor. These data support the utility of LY53857 as a potent and selective tool in probing the 5-HT2 receptor.