The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque

• Published in: Psychopharmacology Vol. 225; no. 1; pp. 21 - 30
• Main Authors: Uslaner, Jason M., Eddins, Donnie, Puri, Vanita, Cannon, Christopher E., Sutcliffe, Jane, Chew, Chan Sing, Pearson, Michelle, Vivian, Jeffrey A., Chang, Ronald K., Ray, William J., Kuduk, Scott D., Wittmann, Marion
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer-Verlag 2013; Springer; Springer Nature B.V
• Subjects: Acetylcholine receptors (muscarinic); Acetylcholine receptors (nicotinic); Acetylcholinesterase; Allosteric properties; Allosteric Regulation; Alzheimer Disease - drug therapy; Alzheimer Disease - physiopathology; Alzheimer's disease; Animals; Biological markers; biomarkers; Biomedical and Life Sciences; Biomedicine; Brain; Brain - blood supply; Brain - drug effects; Care and treatment; Cerebral blood flow; Cerebral circulation; Cognition & reasoning; Cognition - drug effects; Cognition Disorders - drug therapy; Cognition Disorders - etiology; Cognition Disorders - physiopathology; Cognitive ability; Cortex (frontal); Cynomolgus; Disease Models, Animal; Dose-Response Relationship, Drug; Drugs; Female; Macaca fascicularis; Macaca mulatta; Male; Mice; Monkeys & apes; Muscarinic receptors; Neurochemistry; Neurodegenerative diseases; Neurosciences; Original Investigation; Pattern recognition; Pharmacology/Toxicology; Physiological aspects; Piperidines - administration & dosage; Piperidines - pharmacology; Psychiatry; Psychopharmacology; Quinolizines - administration & dosage; Quinolizines - pharmacology; Rats; Rats, Wistar; Receptor, Muscarinic M1 - drug effects; Receptor, Muscarinic M1 - metabolism; Regional Blood Flow - drug effects; Rodents; Scopolamine - toxicity; Side effects; Species Specificity; Translation; Acetylcholine; Cognition; Muscarinic; Working memory; Alzheimer’s disease; Object recognition
• ISSN: 0033-3158; 1432-2072
• DOI: 10.1007/s00213-012-2788-8

Rationale
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.
Objectives
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.