The novel 5-hydroxytryptamine(1A) antagonist LY426965: effects on nicotinewithdrawal and interactions with fluoxetine

LY426965 [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-meth yl-2-phenyl-1-butanone monohydrochloride] is a novel compound with high aff inity for the cloned human 5-hydroxytryptamine (HT)(1A) receptor (K-i = 4.6 6 nM) and 20-fold or greater selectivity over other serotonin and nonseroto nin receptor subtypes. Both in vitro and in vivo studies indicate that LY42 6965 is a full antagonist and has no partial agonist properties. LY426965 d id not stimulate [S-35]guanosine-5'-O-(3-thio) triphosphate (GTP gamma S) b inding to homogenates of cells expressing the cloned human 5-HT1A receptor in vitro but did inhibit 300 nM 5-HT-stimulated [S-35]GTP gamma S binding w ith a K-i value of 3.07 nM. After both p.o. and s.c. administration, LY4269 65 blocked the lower lip retraction, flat body posture, hypothermia, and in crease in rat serum corticosterone induced by the 5-HT1A 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 dis criminative properties. LY426965 completely reversed the effects of nicotin e withdrawal on the auditory startle reflex in rats. In microdialysis exper iments, LY426965 administered together with fluoxetine significantly increa sed extracellular levels of serotonin above those achievable with fluoxetin e alone. In electrophysiological studies, the administration of LY426965 pr oduced 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 effect s of fluoxetine on 5-HT neuronal activity. These preclinical results indica te that LY426965 is a selective, full 5-HT1A antagonist that may have clini cal use as pharmacotherapy for smoking cessation and depression and related disorders.