The M1 Muscarinic Positive Allosteric Modulator PQCA Improves Performance on Translatable Tests of Memory and Attention in Rhesus Monkeys.
| Autor: | Lange HS; Merck & Co., Inc., West Point, Pennsylvania., Cannon CE; Merck & Co., Inc., West Point, Pennsylvania., Drott JT; Merck & Co., Inc., West Point, Pennsylvania., Kuduk SD; Merck & Co., Inc., West Point, Pennsylvania., Uslaner JM; Merck & Co., Inc., West Point, Pennsylvania Jason_Uslaner@merck.com. |
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| Jazyk: | angličtina |
| Zdroj: | The Journal of pharmacology and experimental therapeutics [J Pharmacol Exp Ther] 2015 Dec; Vol. 355 (3), pp. 442-50. Date of Electronic Publication: 2015 Oct 07. |
| DOI: | 10.1124/jpet.115.226712 |
| Abstrakt: | Improved treatment of Alzheimer disease (AD) is a significant unmet medical need that is becoming even more critical given the rise in the number of patients and the substantial economic burden. The current standards of care, acetylcholinesterase inhibitors (AChEIs), are hindered by gastrointestinal side effects owing to their nonselective activation of muscarinic and nicotinic receptors. Recently, the highly selective M1 positive allosteric modulator PQCA (1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl-4-oxo-4 H-quinolizine-3-carboxylic acid) has been demonstrated to improve cognition in a variety of rodent and nonhuman primate cognition models without producing significant gastrointestinal side effects. Here we describe the effect of PQCA and the AChEI donepezil on two clinically relevant and highly translatable touchscreen cognition tasks in nonhuman primates: paired-associates learning (PAL) and the continuous-performance task (CPT). Blockade of muscarinic signaling by scopolamine produced significant impairments in both PAL and CPT. PQCA and donepezil attenuated the scopolamine deficits in both tasks, and the action of these two compounds was similar in magnitude. In addition, the combination of subeffective doses of PQCA and donepezil enhanced PAL performance. These results further suggest that M1-positive allosteric modulators, either as monotherapy or as an add-on to current standards of care, have potential to reduce the cognitive deficits associated with AD. (Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics.) |
| Databáze: | MEDLINE |
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