Vol. 294, Issue 2, 688-700, August 2000

The Novel 5-Hydroxytryptamine_1A Antagonist LY426965: Effects on Nicotine Withdrawal and Interactions with Fluoxetine

Kurt Rasmussen, David O. Calligaro, Janet F. Czachura, Laura J. Dreshfield-Ahmad, David C. Evans, Susan K. Hemrick-Luecke, Mary Jeanne Kallman, William T. Kendrick, J. David Leander, David L. Nelson, Carl D. Overshiner, David B. Wainscott, Mary C. Wolff, David T. Wong, Theresa A. Branchek, John M. Zgombick¹ and Yao-chang Xu

Neuroscience Research, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, Indiana (K.R., D.O.C., J.F.C., L.J.D.-A., D.C.E., S.K.H.-L., M.J.K., W.T.K., J.D.L., D.L.N., C.D.O., D.B.W., M.C.W., D.T.W., Y.-c.X.); and Synaptic Pharmaceutical Corp., Paramus, New Jersey (T.A.B., J.M.Z.)

LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl-2-phenyl-1-butanone monohydrochloride] is a novel compound with high affinity for the cloned human 5-hydroxytryptamine (HT)_1A receptor (K_i = 4.66 nM) and 20-fold or greater selectivity over other serotonin and nonserotonin receptor subtypes. Both in vitro and in vivo studies indicate that LY426965 is a full antagonist and has no partial agonist properties. LY426965 did not stimulate [³⁵S]guanosine-5'-O-(3-thio) triphosphate (GTPS) binding to homogenates of cells expressing the cloned human 5-HT_1A receptor in vitro but did inhibit 300 nM 5-HT-stimulated [³⁵S]GTPS binding with a K_i value of 3.07 nM. After both p.o. and s.c. administration, LY426965 blocked the lower lip retraction, flat body posture, hypothermia, and increase in rat serum corticosterone induced by the 5-HT_1A agonist 8-OH-DPAT (8-hydroxy-2-dipropylaminotetralin). In pigeons, LY426965 dose-dependently blocked the stimulus cue induced by 8-OH-DPAT but had no 8-OH-DPAT-like discriminative properties. LY426965 completely reversed the effects of nicotine withdrawal on the auditory startle reflex in rats. In microdialysis experiments, LY426965 administered together with fluoxetine significantly increased extracellular levels of serotonin above those achievable with fluoxetine alone. In electrophysiological studies, the administration of LY426965 produced a slight elevation of the firing rate of 5-HT neurons in the dorsal raphe nucleus of anesthetized rats and both blocked and reversed the effects of fluoxetine on 5-HT neuronal activity. These preclinical results indicate that LY426965 is a selective, full 5-HT_1A antagonist that may have clinical use as pharmacotherapy for smoking cessation and depression and related disorders.