Pharmacological characterization of LY293284: A 5-HT1A receptor agonist with high potency and selectivity.
(-)-LY293284, (-)-4R-6-acetyl-4-(di-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 Ki of 0.07 nM for the 5-HT1A receptor but no affinity for other monoaminergic receptors within 3 orders of magnitude. LY293284 was evaluated in in vivo models, which have been used as markers for presynaptic and postsynaptic 5-HT1A receptor activity. LY293284 decreased hypothalamic 5-hydroxyindoleacetic acid levels (ED50, 2.9 micrograms/kg s.c.) and dorsal raphe serotonergic neuron firing rate (ED50, 0.08 micrograms/kg s.c.), which are accepted indices of presynaptic activity. LY293284 also induced a reduction in body temperature in rats (ED50, 3.6 micrograms/kg s.c.), which was blocked by pretreatment with (+/-)-pindolol. Hypothermic responses of rats to 5-HT1A agonists have had both pre- and postsynaptic characteristics in previous studies. The ED50 values for 8-hydroxy-2-(di-n-propylamino)-tetralin (8-OH-DPAT) in these tests were 15 to 45 times higher than those observed for LY293284. In models for postsynaptic activity, the ED50 for LY293284 for elevating serum corticosterone levels was 9.7 micrograms/kg s.c. and the minimum effective doses to induce lower lip retraction and flat posture were 3 micrograms/kg s.c. For comparison, the same indices obtained for 8-OH-DPAT were 222.4 and 100 micrograms/kg, respectively. The 5-HT syndrome responses induced by LY293284 were also attenuated by pretreatment with (+/-)-pindolol. LY293284 was 10 times more potent than 8-OH-DPAT in a drug discrimination test that used pigeons trained to identify 8-OH-DPAT. In sexual behavior tests with male rats, LY293284 induced a maximal reduction in ejaculatory latency at 0.01 micrograms/kg s.c., which was approximately 10 times higher potency than 8-OH-DPAT. In the pigeon conflict model for anxiolytic activity, LY293284 was 100 times more potent than 8-OH-DPAT in increasing punished responding. In the rat forced swim model for antidepressant-like activity, LY293284 was 30 and 35 times more potent than 8-OH-DPAT in decreasing immobility time and defecation rate. These studies have demonstrated that LY293284 is a highly selective and extremely potent 5-HT1A receptor agonist and represents a useful pharmacological tool for studying 5-HT1A receptor-mediated effects.
Foreman
M M
MM
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
Fuller
R W
RW
Rasmussen
K
K
Nelson
D L
DL
Calligaro
D O
DO
Zhang
L
L
Barrett
J E
JE
Booher
R N
RN
Paget
C J
CJ
Flaugh
M E
ME
D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology; D001667:Binding, Competitive; D001831:Body Temperature / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D010856:Columbidae; D003345:Corticosterone / Q000097:blood; D006897:Hydroxyindoleacetic Acid / Q000378:metabolism; D008297:Male; D011678:Punishment; D011869:Radioligand Assay; D011903:Raphe Nuclei / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D012726:Sexual Behavior, Animal / Q000187:drug effects; D013312:Stress, Physiological; D014363:Tryptamines / Q000494:pharmacology*
D014151:Anti-Anxiety Agents; D017366:Serotonin Receptor Agonists; D014363:Tryptamines; C089776:LY 293284; D006897:Hydroxyindoleacetic Acid; D003345:Corticosterone