title: The M1 Muscarinic Positive Allosteric Modulator PQCA Improves Performance on Translatable Tests of Memory and Attention in Rhesus Monkeys.
abstract: 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.
authors.affiliation: Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Henry S
authors.initials: HS
authors.lastname: Lange
authors.affiliation: Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Cannon
authors.affiliation: Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Drott
authors.affiliation: Merck & Co., Inc., West Point, Pennsylvania.
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.affiliation: Merck & Co., Inc., West Point, Pennsylvania Jason_Uslaner@merck.com.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects; D001288:Attention / Q000187:drug effects*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects; D000077265:Donepezil; D004305:Dose-Response Relationship, Drug; D007189:Indans / Q000494:pharmacology; D008253:Macaca mulatta; D008297:Male; D008568:Memory / Q000187:drug effects*; D018721:Muscarinic Agonists / Q000494:pharmacology*; D018727:Muscarinic Antagonists / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology*; D011597:Psychomotor Performance / Q000187:drug effects*; D011807:Quinolizines / Q000494:pharmacology*; D043643:Receptor, Muscarinic M1 / Q000187:drug effects*; D012601:Scopolamine / Q000494:pharmacology
chemical_list: C581536:1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; D002800:Cholinesterase Inhibitors; D007189:Indans; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D010880:Piperidines; D011807:Quinolizines; D043643:Receptor, Muscarinic M1; D000077265:Donepezil; D012601:Scopolamine