Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey

Rationale 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....

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Bibliographic Details
Published in:	Psychopharmacology Vol. 232; no. 11; pp. 1859 - 1866
Main Authors:	Vardigan, Joshua D., Cannon, Christopher E., Puri, Vanita, Dancho, Mandy, Koser, AmyJo, Wittmann, Marion, Kuduk, Scott D., Renger, John J., Uslaner, Jason M.
Format:	Journal Article
Language:	English
Published:	Berlin/Heidelberg Springer Berlin Heidelberg 01-06-2015 Springer Springer Nature B.V
Subjects:	Aged Alzheimer Disease - drug therapy Alzheimer's disease Animal cognition Animals Appetitive Behavior - drug effects Attention - drug effects Biomedical and Life Sciences Biomedicine Cognition Cognition - drug effects Complications and side effects Defecation - drug effects Donepezil Dosage and administration Drug therapy Female Humans Indans - pharmacology Indans - toxicity Macaca mulatta Male Monkeys & apes Muscarinic Agonists - pharmacology Neuropsychological Tests Neurosciences Orientation - drug effects Original Investigation Pharmacology/Toxicology Piperidines - pharmacology Piperidines - toxicity Problem Solving - drug effects Psychiatry Psychopharmacology Pyridines - pharmacology Pyridines - toxicity Quinolizines - pharmacology Quinolizines - toxicity Receptor, Muscarinic M1 - drug effects Salivation - drug effects Side effects Thiadiazoles - pharmacology Thiadiazoles - toxicity United States Xanomeline Muscarinic M1 Donepezil Side-effects Cognition Acetylcholinesterase Alzheimer’s
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Summary:	Rationale 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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0033-3158 1432-2072
DOI:	10.1007/s00213-014-3813-x