PHARMACOLOGICAL CHARACTERIZATION OF LY293284 - A 5-HT1A RECEPTOR AGONIST WITH HIGH POTENCY AND SELECTIVITY

(-)-LY293284, -n-propylamino)-1,3,4,5-tetrahydrobenz[c,d]indole, is a conformationally restricted tryptamine derivative with an acetyl group serving as a protophilic substitution for the hydroxyl in serotonin ( 5-HT). In ligand displacement studies, LY293284 had a K-I of 0.07 nM f or the 5-HT1A receptor but no affinity for other monoaminergic recepto rs within 3 orders of magnitude. LY293284 was evaluated in in vivo mod els, which have been used as markers for presynaptic and postsynaptic 5-HT1A receptor activity. LY293284 decreased hypothalamic 5-hydroxyind oleacetic acid levels (ED(50), 2.9 mu g/kg s.c.) and dorsal raphe sero tonergic neuron firing rate (ED(50), 0.08 mu g/kg s.c.), which are acc epted indicies of presynaptic activity. LY293284 also induced a reduct ion in body temperature in rats (ED(50), 3.6 mu g/kg s.c.), which was blocked by pretreatment with (+/-)-pindolol. Hypothermic responses of rats to 5-HT1A agonists have had both pre- and postsynaptic characteri stics in previous studies. The ED(50) values for 8-hydroxy-2-(di-n-pro pylamino)-tetralin (8-OH-DPAT) in these tests were 15 to 45 times high er than those observed for LY293284. In models for postsynaptic activi ty, the ED(50) for LY293284 for elevating serum corticosterone levels was 9.7 mu g/kg s.c. and the minimum effective doses to induce lower l ip retraction and flat posture were 3 mu g/kg s.c. For comparison, the same indices obtained for 8-OH-DPAT were 222.4 and 100 mu g/kg, respe ctively. The 5-HT syndrome responses induced by LY293284 were also att enuated by pretreatment with (+/-)-pindolol. LY293284 was 10 times mor e potent than 8-OH-DPAT in a drug discrimination test that used pigeon s trained to identify 8-OH-DPAT. In sexual behavior tests with male ra ts, LY293284 induced a maximal reduction in ejaculatory latency at 0.0 1 mu g/kg s.c., which was approximately 10 times higher potency than 8 -OH-DPAT. In the pigeon conflict model for anxiolytic activity, LY2932 84 was 100 times more potent than 8-OH-DPAT in increasing punished res ponding. In the rat forced swim model for antidepressant-like activity , LY293284 was 30 and 35 times more potent than 8-OH-DPAT in decreasin g immobility time and defecation rate. These studies have demonstrated that LY293284 is a highly selective and extremely potent 5-HT1A recep tor agonist and represents a useful pharmacological tool for studying 5-HT1A receptor-mediated effects.