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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).

Hirst WD, Andree TH, Aschmies S, Childers WE, Comery TA, Dawson LA, Day M, Feingold IB, Grauer SM, Harrison BL, Hughes ZA, Kao J, Kelly MG, van der Lee H, Rosenzweig-Lipson S, Saab AL, Smith DL, Sullivan K, Rizzo SJ, Tio C, Zhang MY, Schechter LE

Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543, USA. hirstw@wyeth.com

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.

Published 18 March 2008 in J Pharmacol Exp Ther, 325(1): 134-45.
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