Abstract
5-Hydroxytryptamine (5-HT)1A receptors play an important role in multiple cognitive processes, and compelling evidence suggests that 5-HT1A antagonists can reverse cognitive impairment. We have examined the therapeutic potential of a potent (Ki = 1.1 nM), selective (>100-fold), orally bioavailable, silent 5-HT1A receptor antagonist (KB = 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-HT1A 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-HT1A receptor “silent” antagonist that is effective in preclinical memory paradigms at doses where approximately 90% of the postsynaptic 5-HT1A 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.
Footnotes
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Parts of this work were presented previously at the following meetings: Schechter LE, Smith DL, Rosenzweig-Lipson S, Marquis K, Jones D, Nguyen HQ, Dawson LA, and Kelly MG (2000) Pharmacological characterization of an orally active 5-HT1A receptor antagonist: WAY-405. The 30th Annual Meeting of the Society for Neuroscience; 2000 Nov 4–9; New Orleans, LA; and Hirst WD, Andree TH, Aschmies S, Childers W, Comery TA, Day M, Grauer SM, Hughes ZA, van der Lee H, Rosenzweig-Lipson S, et al. (2006) A novel silent 5-HT1A receptor antagonist has efficacy in multiple rat cognition models. The 36th Annual Meeting of the Society for Neuroscience; 2006 Oct 14–18; Atlanta, GA. Society for Neuroscience, Washington DC.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.107.133082.
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ABBREVIATIONS: 5-HT, 5-hydroxytryptamine; 8-OH-DPAT, 8-hydroxy-2-dipropylaminotetralin; WAY-100635, N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide trihydrochloride; WAY-100135, N-tert-butyl-3-[4-(2-methoxyphenyl)piperazin-1-yl]-2-phenylpropanamide; WAY-101405, (R)-N-(2-methyl-(4-indolyl-1-piperazinyl)ethyl)-N-(2-pyridinyl)-cyclohexane carboxamide; NAD-299, (R)-3-N,N-dicyclobutylamino-8-fluoro-3,4-dihydro-2H-1-benzopyran-5-carboxamide hydrogen (2R,3R)-tartrate monohydrate; MK-801, (–)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate; h, human; r, rat; CHO, Chinese hamster ovary; HPLC, high-performance liquid chromatography; ANOVA, analysis of variance; LSD, least significant difference; BP, binding potential; BMY 7378, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4,5]decane-7,9-dione 2HCl; AUC, area under the curve; LY-426965, [(2S)-(+)-1-cyclohexyl-4-[4-(2-methoxyphenyl)-1-piperazinyl]2-methyl-2-phenyl-1-butanone monohydrochloride].
- Received October 15, 2007.
- Accepted January 7, 2008.
- The American Society for Pharmacology and Experimental Therapeutics
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