Pharmacological profile of LY301317, a potent and selective 5-HT1A agonist

LY301317 ((4r)-(−)-4-(dipropylamino)-6-(5-oxazolinyl)-1,3,4,5-tetrahydrobenz[c,d]indole) has high affinity for the 5-HT_1A receptor and weak affinity for the 5-HT_1D and histamine-H₁ receptors. No significant affinity was found for the other amine receptors studied. In rats, LY301317 produced potent in vivo effects that are characteristic of compounds with agonist activity at the 5-HT_1A receptor, such as an increase in serum corticosterone concentration, a reduction in 5-HIAA concentration in brain tissue, induction of flat body posture and lower lip retraction (components of a serotonin syndrome), and a decrease of core body temperature. In pigeons trained to discriminate 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) from saline, full generalization to LY301317 was observed. LY301317 increased punished responding in both the pigeon and rat conflict tests for anxiolytic activity. LY301317 reduced immobility in the rat forced swim model used to indicate potential antidepressant activity. In pigeons, LY301317 blocked emesis induced by a chemical (ditolyguanidine), by a 5-HT₃ agonist (m-(chlorophenyl)-biguanide), and by an oncolytic agent (cisplatin), as well as vomiting induced by conditioning to environmental stimuli (a model of anticipatory nausea and vomiting). In addition, LY301317 blocked cisplatin- and ipecac-induced vomiting in the dog and motion-induced emesis in the cat. It was concluded that LY301317 is an orally active, potent, and selective agonist for the 5-HT_1A receptor with potential clinical utility as an anxiolytic, an antidepressant, and a broad-spectrum antiemetic. Drug Dev. Res. 40:17–34, 1997. © 1997 Wiley-Liss, Inc.