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

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Abstract

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.

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Acknowledgments

The authors would like to thank the Merck Bioanalytic group for analyzing plasma exposures for these studies. JU, DE, VP, CC, MP, RC, and SK are current employees of Merck and Co., Inc. (USA) and potentially own stock and/or stock options in the company.

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Author notes

  1. William J. Ray

    Present address: Envoy Therapeutics, Jupiter, FL, 33458, USA

  2. Marion Wittmann

    Present address: Biogen Idec, Cambridge, MA, 02142, USA

Authors and Affiliations

  1. Merck Research Laboratories, Merck & Co., Inc., West Point, PA, 19486, USA

    Jason M. Uslaner, Donnie Eddins, Vanita Puri, Christopher E. Cannon, Michelle Pearson, Ronald K. Chang & Scott D. Kuduk

  2. Maccine, Science Park II, Singapore

    Jane Sutcliffe, Chan Sing Chew & Jeffrey A. Vivian

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  1. Jason M. Uslaner
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  2. Donnie Eddins
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Correspondence to Jason M. Uslaner.

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Uslaner, J.M., Eddins, D., Puri, V. et al. The muscarinic M1 receptor positive allosteric modulator PQCA improves cognitive measures in rat, cynomolgus macaque, and rhesus macaque. Psychopharmacology 225, 21–30 (2013). https://doi.org/10.1007/s00213-012-2788-8

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