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).
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.
Hirst
Warren D
WD
Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. hirstw@wyeth.com
Andree
Terrance H
TH
Aschmies
Suzan
S
Childers
Wayne E
WE
Comery
Thomas A
TA
Dawson
Lee A
LA
Day
Mark
M
Feingold
Irene B
IB
Grauer
Steven M
SM
Harrison
Boyd L
BL
Hughes
Zoë A
ZA
Kao
John
J
Kelly
Michael G
MG
van der Lee
Heidi
H
Rosenzweig-Lipson
Sharon
S
Saab
Annmarie L
AL
Smith
Deborah L
DL
Sullivan
Kelly
K
Rizzo
Stacey J Sukoff
SJ
Tio
Cesario
C
Zhang
Mei-Yi
MY
Schechter
Lee E
LE
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*
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