The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque
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- 作者：Jason M. Uslaner (1)
Donnie Eddins (1)
Vanita Puri (1)
Christopher E. Cannon (1)
Jane Sutcliffe (2)
Chan Sing Chew (2)
Michelle Pearson (1)
Jeffrey A. Vivian (2)
Ronald K. Chang (1)
William J. Ray (3)
Scott D. Kuduk (1)
Marion Wittmann (4) - 关键词：Alzheimer’s disease ; Acetylcholine ; Muscarinic ; Cognition ; Object recognition ; Working memory
- 刊名：Psychopharmacology
- 出版年：2013
- 出版时间：January 2013
- 年：2013
- 卷：225
- 期：1
- 页码：21-30
- 全文大小：299KB
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Donnie Eddins (1)
Vanita Puri (1)
Christopher E. Cannon (1)
Jane Sutcliffe (2)
Chan Sing Chew (2)
Michelle Pearson (1)
Jeffrey A. Vivian (2)
Ronald K. Chang (1)
William J. Ray (3)
Scott D. Kuduk (1)
Marion Wittmann (4)
1. Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA
2. Maccine, Science Park II, Singapore
3. Envoy Therapeutics, Jupiter, FL, 33458, USA
4. Biogen Idec, Cambridge, MA, 02142, USA - ISSN：1432-2072
文摘
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.