• Joshua D Vardigan, Christopher E Cannon, Vanita Puri, Mandy Dancho, AmyJo Koser, Marion Wittmann, Scott D Kuduk, John J Renger, and Jason M Uslaner.
• Merck & Co., Inc., WP44E-200 770 Sumneytown Pike, West Point, PA, 19486, USA.
• Psychopharmacology (Berl.). 2015 Jun 1; 232 (11): 1859-66.

RationaleThe 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.MethodsWe 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.ResultsAll 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.ConclusionsThese 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.

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