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.