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Improved cognition without adverse effects: novel M1 muscarinic potentiator compares favorably to donepezil and xanomeline in rhesus monkey.
- Source :
-
Psychopharmacology [Psychopharmacology (Berl)] 2015 Jun; Vol. 232 (11), pp. 1859-66. Date of Electronic Publication: 2014 Dec 10. - Publication Year :
- 2015
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Abstract
- 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.<br />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.<br />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.<br />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.
- Subjects :
- Aged
Alzheimer Disease drug therapy
Animals
Appetitive Behavior drug effects
Attention drug effects
Defecation drug effects
Donepezil
Female
Humans
Indans toxicity
Macaca mulatta
Male
Neuropsychological Tests
Orientation drug effects
Piperidines toxicity
Problem Solving drug effects
Pyridines toxicity
Quinolizines toxicity
Salivation drug effects
Thiadiazoles toxicity
Cognition drug effects
Indans pharmacology
Muscarinic Agonists pharmacology
Piperidines pharmacology
Pyridines pharmacology
Quinolizines pharmacology
Receptor, Muscarinic M1 drug effects
Thiadiazoles pharmacology
Subjects
Details
- Language :
- English
- ISSN :
- 1432-2072
- Volume :
- 232
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Psychopharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25491927
- Full Text :
- https://doi.org/10.1007/s00213-014-3813-x