Abstract

LY228729 is a conformationally restricted tryptamine derivative with a carboxamide serving as a protophilic group to mimic the hydroxyl in serotonin (5-HT). LY228729 has high affinity for the 5-HT1A receptor, weak affinity for the 5-HT1D receptor and no significant affinity for other monoaminergic receptors studied. LY228729 was less effective than 5-carboxamidotrytamine in suppressing K(+)-evoked release of 3H-5-HT from parietal-occipital cortical slices from guinea pigs, which is in agreement with its weak 5-HT1D receptor affinity. LY228729 reduced hypothalamic 5-hydroxyindole-3-acetic acid levels and increased serum corticosterone levels in rats. LY228729 reduced hypothalamic 5-hydroxytryptophan 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 10 times higher) and these effects were blocked by (+/-) pindolol. LY228729 induced a hypothermic response in rats, which was blocked by (+/-) pindolol. These in vivo responses are characteristics of compounds with 5-HT1A agonist activity. In the preclinical efficacy models, LY228729 suppressed motion sickness responses in cats; decreased ejaculatory latency and the increased copulatory efficiency and rate in rats and increased punished responding at lower doses than it lowered unpunished responding in rats. Collectively, 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 previously have antidepressant activity, this indication will also be evaluated.