PHARMACOLOGICAL CHARACTERIZATION OF ENANTIOMERS OF 8-THIOMETHYL-2-(DI-N-PROPYLAMINO)TETRALIN, POTENT AND SELECTIVE 5-HT1A RECEPTOR AGONISTS

LY274600 and LY274601 are the S (-) and R (+) enantiomers, respectivel y, of 8-thiomethyl-2-(di-n-propylamino)tetralin (8-OH-DPAT). In in vit ro studies, both enantiomers have high and selective affinity for the 5-HT1A receptor. However, LY274600 produced submaximal inhibition of f orskolin-stimulated cyclase activity, which indicates that it is a par tial agonist, whereas LY274601 produced maximal inhibition of cyclase activity, which indicates that it is a full agonist in this model. Bot h of these enantiomers had potent in vivo pharmacological effects in r ats that are characteristic of 5-HT,, receptor agonists including (1) a reduction of hypothalamic 5-HIAA levels, (2) an increase in serum co rticosterone levels, (3) a reduction in hypothalamic 5-HTP accumulatio n after decarboxylase inhibition, (4) an induction of 5-HT1A behaviora l responses, e.g., flat posture and lower lip retraction, and (5) a lo wering of body temperature. In these general pharmacological tests, bo th compounds had a potency equal to or greater than 8-OH-DPAT but had a greater oral activity. LY274601 appeared to be either slightly more potent or efficacious than LY274600. In the drug-discrimination studie s using pigeons trained to identify the effects of 8-OH-DPAT, LY274601 was significantly here potent than LY274600, but both were less poten t than 8-OH-DPAT. Both enantiomers restored full sexual reflex functio n to rats that had reduced sexual capacity. In rats with normal capaci ty for sexual reflexes but reduced performance, the enantiomers caused decreases in ejaculatory latencies and postejaculatory latencies and increases in copulatory efficiency and rate. No consistent differences between the enantiomers could be demonstrated in these estimates of t otal sexual performance, erectile capacity, and sexual drive. Both ena ntiomers increased punished responding at lower doses than were needed to decrease unpunished responding in pigeons, an effect that is indic ative of anxiolytic activity. LY274600, a partial agonist, produced a significantly greater change in punished responding than did LY274601, a full agonist. Both compounds induced dose-related decreases in immo bility time and defecation rate in the rat forced swim model, which re present reductions in stress-induced ''behavioral despair'' and stress -induced gastrointestinal motility. Collectively, these pharmacologica l studies have shown that the substitution of a thiomethyl for the hyd roxyl group at the 8 position on the 2-(di-n-propylamino) tetralin str ucture resulted in selective and potent agonists for the 5-HT1A recept or similar to that of 8-OH-DPAT but with improved oral potency. The pr eclinical efficacy studies demonstrated possible utilities for these c ompounds in the treatment of either sexual response disorders, anxiety , or depression. (C) 1995 Wiley-Liss, Inc.