title: The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque.
abstract: BACKGROUND
  The current standards of care for Alzheimer's disease, acetylcholinesterase inhibitors, have limited efficacy due to a host of mechanism-related side effects arising from indiscriminate activation of muscarinic and nicotinic receptors. The M1 muscarinic receptor is predominantly expressed in the brain in regions involved in cognition, and therefore selective activation of the M1 receptor would be expected to boost cognitive performance with reduced risk of peripheral side effects.
  
  
  OBJECTIVE
  Here we investigated whether the selective M1 muscarinic receptor positive allosteric modulator, PQCA, improves cognitive performance and cerebral blood flow.
  
  
  RESULTS
  PQCA attenuated a scopolamine-induced deficit in novel object recognition in rat, self-ordered spatial search in cynomolgus macaque, and the object retrieval detour task in rhesus macaque. Beneficial effects in each of these assays and species were observed at similar plasma drug concentrations. Furthermore, at similar drug concentrations that were effective in the behavioral studies, PQCA increased blood flow in the frontal cortex of mice, providing a translational biomarker that could be used to guide dose selection for clinical studies.
  
  
  CONCLUSIONS
  These findings provide a framework for appropriately testing an M1 selective compound in patients with Alzheimer's disease.
authors: Merck Research Laboratories, Merck & Co., Inc., West Point, PA 19486, USA. Jason_Uslaner@merck.com
authors: Jason M
authors: JM
authors: Uslaner
authors: Donnie
authors: D
authors: Eddins
authors: Vanita
authors: V
authors: Puri
authors: Christopher E
authors: CE
authors: Cannon
authors: Jane
authors: J
authors: Sutcliffe
authors: Chan Sing
authors: CS
authors: Chew
authors: Michelle
authors: M
authors: Pearson
authors: Jeffrey A
authors: JA
authors: Vivian
authors: Ronald K
authors: RK
authors: Chang
authors: William J
authors: WJ
authors: Ray
authors: Scott D
authors: SD
authors: Kuduk
authors: Marion
authors: M
authors: Wittmann
mesh_terms: D000494:Allosteric Regulation; D000544:Alzheimer Disease / Q000188:drug therapy / Q000503:physiopathology; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D005260:Female; D008252:Macaca fascicularis; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D010880:Piperidines / Q000008:administration & dosage / Q000494:pharmacology*; D011807:Quinolizines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D043643:Receptor, Muscarinic M1 / Q000187:drug effects* / Q000378:metabolism; D012039:Regional Blood Flow / Q000187:drug effects; D012601:Scopolamine / Q000633:toxicity; D013045:Species Specificity
chemical_list: C581536:1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; D010880:Piperidines; D011807:Quinolizines; D043643:Receptor, Muscarinic M1; D012601:Scopolamine