PRECLINICAL STUDIES ON LY228729 - A POTENT AND SELECTIVE SEROTONIN(1A) AGONIST

LY228729 is a conformationally restricted tryptamine derivative with a carboxamide serving as a protophilic group to mimic the hydroxyl in s erotonin (5-HT). LY228729 has high affinity for the 5-HT1A receptor, w eak affinity for the 5-HT1D receptor and no significant affinity for o ther monoaminergic receptors studied. LY228729 was less effective than 5-carboxamidotrytamine in suppressing K+-evoked release of H-3-5-HT f rom parietal-occipital cortical slices from guinea pigs, which is in a greement with its weak 5-HT1D receptor affinity. LY228729 reduced hypo thalamic 5-hydroxyindole-3-acetic acid levels and increased serum cort icosterone levels in rats. LY228729 reduced hypothalamic 5-hydroxytryp tophan accumulation after decarboxylase inhibition. LY228729 increased flat posture and lower lip retraction scores in rats at doses between 0.1 and 1 mg/kg s.c. (p.o. doses were 1 0 times higher) and these eff ects were blocked by (+/-) pindolol. LY228729 induced a hypothermic re sponse in rats, which was blocked by (+/-) pindolol. These in vivo res ponses are characteristics of compounds with 5-HT1A agonist activity. In the preclinical efficacy models, LY228729 suppressed motion sicknes s responses in cats; decreased ejaculatory latency and the increased c opulatory efficiency and rate in rats and increased punished respondin g at lower doses than it lowered unpunished responding in rats. Collec tively, these results indicate that LY228729 is potent 5-HT1A agonist with bioavailability properties sufficient for clinical evaluation and with efficacy in preclinical models of anxiety, sexual disorders and motion sickness. Since the 5-HT1A agonists that have been studied prev iously have antidepressant activity, this indication will also be eval uated.