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NEUROPHARMACOLOGY

Correlating Efficacy in Rodent Cognition Models with in Vivo 5-Hydroxytryptamine_1A Receptor Occupancy by a Novel Antagonist, (R)-N-(2-Methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane Carboxamide (WAY-101405)

Discovery Neuroscience (W.D.H., T.H.A., S.A., T.A.C., L.A.D., M.D., S.M.G., Z.A.H., H.v.d.L., S.R.-L., D.L.S., K.S., S.J.S.R., L.E.S.) and Chemical and Screening Sciences (W.E.C., B.L.H., M.G.K., A.L.S., M.-Y.Z.), Wyeth Research, Princeton, New Jersey; and Drug Safety and Metabolism, Wyeth Research, Collegeville, Pennsylvania (I.B.F., J.K., C.T.)

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 [³H]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 ED₅₀ 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.

Address correspondence to: Dr. Warren D. Hirst, Discovery Neuroscience, Wyeth Research, CN 8000, Princeton, NJ 08543. E-mail: hirstw{at}wyeth.com