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)

The Journal of Pharmacology and Experimental Therapeutics
Warren D HirstL E Schechter

Abstract

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, administere...Continue Reading

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Citations

Sep 3, 2013·Psychopharmacology·Thomas FreretMichel Boulouard
Dec 4, 2013·Journal of Medicinal Chemistry·Ferdinando FiorinoElisa Perissutti
May 3, 2011·Expert Opinion on Drug Discovery·Altaf S DarveshCornelis J Van der Schyf
Jul 7, 2012·Progress in Neurobiology·José Julio RodríguezAlexei Verkhratsky
Feb 15, 2011·Pharmacology, Biochemistry, and Behavior·Alvin V TerryScott J Webster
Apr 24, 2010·European Neuropsychopharmacology : the Journal of the European College of Neuropsychopharmacology·Jan KehrSven Ove Ogren
Mar 25, 2009·Pharmacology & Therapeutics·Sarah Grimwood, Paul R Hartig
Aug 19, 2008·Behavioural Brain Research·Herbert Y Meltzer, Tomiki Sumiyoshi
Mar 1, 2013·Angewandte Chemie·Jacques-Alexis Funel, Stefan Abele
May 14, 2009·The International Journal of Neuropsychopharmacology·Stacey J Sukoff RizzoSharon Rosenzweig-Lipson
Feb 23, 2010·Pharmacology, Biochemistry, and Behavior·Miguel SkirzewskiPedro Rada
Jul 14, 2021·Future Medicinal Chemistry·Agnieszka JankowskaGrażyna Chłoń-Rzepa

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