title: Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey.
abstract: BACKGROUND
  The standards of care for Alzheimer's disease, acetylcholinesterase inhibitors such as donepezil (Aricept®), are dose-limited due to adverse side-effects. These adverse events lead to significant patient non-compliance, constraining the dose and magnitude of efficacy that can be achieved. Non-selective muscarinic receptor orthosteric agonists such as Xanomeline have been shown to be effective in treating symptoms as well, but were also poorly tolerated. Therefore, there is an unmet medical need for a symptomatic treatment that improves symptoms and is better tolerated.
  
  
  METHODS
  We compared donepezil, xanomeline, and the novel selective muscarinic 1 receptor positive allosteric modulator PQCA in combination with donepezil in the object retrieval detour (ORD) cognition test in rhesus macaque. Gastrointestinal (GI) side effects (salivation and feces output) were then assessed with all compounds to determine therapeutic window.
  
  
  RESULTS
  All three compounds significantly reduced a scopolamine-induced deficit in ORD. Consistent with what is observed clinically in patients, both donepezil and xanomeline produced significant GI effects in rhesus at doses equal to or less than a fivefold margin from the minimum effective dose that improves cognition. In stark contrast, PQCA produced no GI side effects when tested at the same dose range.
  
  
  CONCLUSIONS
  These data suggest M1 positive allosteric modulators have the potential to improve cognition in Alzheimer's disease with a greater therapeutic margin than the current standard of care, addressing an important unmet medical need.
authors.affiliation: Merck & Co., Inc., WP44E-200 770 Sumneytown Pike, West Point, PA, 19486, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Vardigan
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Cannon
authors.forename: Vanita
authors.initials: V
authors.lastname: Puri
authors.forename: Mandy
authors.initials: M
authors.lastname: Dancho
authors.forename: AmyJo
authors.initials: A
authors.lastname: Koser
authors.forename: Marion
authors.initials: M
authors.lastname: Wittmann
authors.forename: Scott D
authors.initials: SD
authors.lastname: Kuduk
authors.forename: John J
authors.initials: JJ
authors.lastname: Renger
authors.forename: Jason M
authors.initials: JM
authors.lastname: Uslaner
mesh_terms: D000368:Aged; D000544:Alzheimer Disease / Q000188:drug therapy; D000818:Animals; D001070:Appetitive Behavior / Q000187:drug effects; D001288:Attention / Q000187:drug effects; D003071:Cognition / Q000187:drug effects*; D003672:Defecation / Q000187:drug effects; D000077265:Donepezil; D005260:Female; D006801:Humans; D007189:Indans / Q000494:pharmacology* / Q000633:toxicity; D008253:Macaca mulatta; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D009483:Neuropsychological Tests; D009949:Orientation / Q000187:drug effects; D010880:Piperidines / Q000494:pharmacology* / Q000633:toxicity; D011340:Problem Solving / Q000187:drug effects; D011725:Pyridines / Q000494:pharmacology* / Q000633:toxicity; D011807:Quinolizines / Q000494:pharmacology* / Q000633:toxicity; D043643:Receptor, Muscarinic M1 / Q000187:drug effects*; D012472:Salivation / Q000187:drug effects; D013830:Thiadiazoles / Q000494:pharmacology* / Q000633:toxicity
chemical_list: C581536:1-((4-cyano-4-(pyridine-2-yl)piperidin-1-yl)methyl)-4-oxo-4H-quinolizine-3-carboxylic acid; D007189:Indans; D018721:Muscarinic Agonists; D010880:Piperidines; D011725:Pyridines; D011807:Quinolizines; D043643:Receptor, Muscarinic M1; D013830:Thiadiazoles; D000077265:Donepezil; C075257:xanomeline