title: Correlating efficacy in rodent cognition models with in vivo 5-hydroxytryptamine1a receptor occupancy by a novel antagonist, (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405).
abstract: 5-Hydroxytryptamine (5-HT)(1A) receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT(1A) antagonists can reverse cognitive impairment. We have examined the therapeutic potential of a potent (K(i) = 1.1 nM), selective (>100-fold), orally bioavailable, silent 5-HT(1A) receptor antagonist (K(B) = 1.3 nM) (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)-ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide (WAY-101405). Oral administration of WAY-101405 was shown to be effective in multiple rodent models of learning and memory. In a novel object recognition paradigm, 1 mg/kg enhanced retention (memory) for previously learned information, and it was able to reverse the memory deficits induced by scopolamine. WAY-101405 (1 mg/kg) was also able to reverse scopolamine-induced deficits in a rat contextual fear conditioning model. In the Morris water maze, WAY-101405 (3 mg/kg) significantly improved learning in a paradigm of increasing task difficulty. In vivo microdialysis studies in the dorsal hippocampus of freely moving adult rats demonstrated that acute administration of WAY-101405 (10 mg/kg) increased extracellular acetylcholine levels. The selective radioligand [(3)H]WAY-100635, administered i.v., was used for in vivo receptor occupancy studies, where WAY-101405 occupied 5-HT(1A) receptors in the rat cortex, with an ED(50) value of 0.1 mg/kg p.o. Taken together, these studies demonstrate that WAY-101405 is a potent and selective, brain penetrant, orally bioavailable 5-HT(1A) receptor "silent" antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT(1A) receptors are occupied. These results further support the rationale for use of this compound class in the treatment of cognitive dysfunction associated with psychiatric and neurological conditions.
authors.affiliation: Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. hirstw@wyeth.com
authors.forename: Warren D
authors.initials: WD
authors.lastname: Hirst
authors.forename: Terrance H
authors.initials: TH
authors.lastname: Andree
authors.forename: Suzan
authors.initials: S
authors.lastname: Aschmies
authors.forename: Wayne E
authors.initials: WE
authors.lastname: Childers
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Comery
authors.forename: Lee A
authors.initials: LA
authors.lastname: Dawson
authors.forename: Mark
authors.initials: M
authors.lastname: Day
authors.forename: Irene B
authors.initials: IB
authors.lastname: Feingold
authors.forename: Steven M
authors.initials: SM
authors.lastname: Grauer
authors.forename: Boyd L
authors.initials: BL
authors.lastname: Harrison
authors.forename: Zoë A
authors.initials: ZA
authors.lastname: Hughes
authors.forename: John
authors.initials: J
authors.lastname: Kao
authors.forename: Michael G
authors.initials: MG
authors.lastname: Kelly
authors.forename: Heidi
authors.initials: H
authors.lastname: van der Lee
authors.forename: Sharon
authors.initials: S
authors.lastname: Rosenzweig-Lipson
authors.forename: Annmarie L
authors.initials: AL
authors.lastname: Saab
authors.forename: Deborah L
authors.initials: DL
authors.lastname: Smith
authors.forename: Kelly
authors.initials: K
authors.lastname: Sullivan
authors.forename: Stacey J Sukoff
authors.initials: SJ
authors.lastname: Rizzo
authors.forename: Cesario
authors.initials: C
authors.lastname: Tio
authors.forename: Mei-Yi
authors.initials: MY
authors.lastname: Zhang
authors.forename: Lee E
authors.initials: LE
authors.lastname: Schechter
mesh_terms: D000631:Aminopyridines / Q000494:pharmacology*; D000818:Animals; D001682:Biological Availability; D001921:Brain / Q000378:metabolism; D003071:Cognition / Q000187:drug effects*; D003510:Cyclohexanes / Q000494:pharmacology*; D008568:Memory / Q000187:drug effects; D023421:Models, Animal; D010879:Piperazines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000494:pharmacology*
chemical_list: D000631:Aminopyridines; D003510:Cyclohexanes; C514231:N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexane carboxamide; D010879:Piperazines; D058829:Serotonin 5-HT1 Receptor Antagonists; D012702:Serotonin Antagonists