title: The novel 5-Hydroxytryptamine(1A) antagonist LY426965: effects on nicotine withdrawal and interactions with fluoxetine.
abstract: 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 [(35)S]guanosine-5'-O-(3-thio) triphosphate (GTPgammaS) binding to homogenates of cells expressing the cloned human 5-HT(1A) receptor in vitro but did inhibit 300 nM 5-HT-stimulated [(35)S]GTPgammaS 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.
authors.affiliation: Neuroscience Research, Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46285, USA. rasmussen.kurt@lilly.com
authors.forename: K
authors.initials: K
authors.lastname: Rasmussen
authors.forename: D O
authors.initials: DO
authors.lastname: Calligaro
authors.forename: J F
authors.initials: JF
authors.lastname: Czachura
authors.forename: L J
authors.initials: LJ
authors.lastname: Dreshfield-Ahmad
authors.forename: D C
authors.initials: DC
authors.lastname: Evans
authors.forename: S K
authors.initials: SK
authors.lastname: Hemrick-Luecke
authors.forename: M J
authors.initials: MJ
authors.lastname: Kallman
authors.forename: W T
authors.initials: WT
authors.lastname: Kendrick
authors.forename: J D
authors.initials: JD
authors.lastname: Leander
authors.forename: D L
authors.initials: DL
authors.lastname: Nelson
authors.forename: C D
authors.initials: CD
authors.lastname: Overshiner
authors.forename: D B
authors.initials: DB
authors.lastname: Wainscott
authors.forename: M C
authors.initials: MC
authors.lastname: Wolff
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: T A
authors.initials: TA
authors.lastname: Branchek
authors.forename: J M
authors.initials: JM
authors.lastname: Zgombick
authors.forename: Y C
authors.initials: YC
authors.lastname: Xu
mesh_terms: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000037:antagonists & inhibitors / Q000494:pharmacology; D000161:Acoustic Stimulation; D000818:Animals; D001831:Body Temperature / Q000187:drug effects; D010856:Columbidae; D003345:Corticosterone / Q000097:blood; D003863:Depression / Q000188:drug therapy; D004193:Discrimination Learning / Q000187:drug effects; D004347:Drug Interactions; D005473:Fluoxetine / Q000494:pharmacology*; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D008046:Lip / Q000187:drug effects; D008297:Male; D017551:Microdialysis; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D009538:Nicotine / Q000009:adverse effects*; D010880:Piperidines / Q000494:pharmacology*; D011187:Posture; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D044263:Receptors, Serotonin, 5-HT1; D013216:Reflex, Startle / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D016540:Smoking Cessation; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy* / Q000209:etiology; D013462:Sulfur Radioisotopes
chemical_list: D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D003345:Corticosterone; D005473:Fluoxetine; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D009538:Nicotine; D010880:Piperidines; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D013462:Sulfur Radioisotopes; C412310:LY 426965