PT  - JOURNAL ARTICLE
AU  - Jason M. Uslaner
AU  - Scott D. Kuduk
AU  - Marion Wittmann
AU  - Henry S. Lange
AU  - Steve V. Fox
AU  - Chris Min
AU  - Natasa Pajkovic
AU  - Dawn Harris
AU  - Caroline Cilissen
AU  - Chantal Mahon
AU  - Kate Mostoller
AU  - Steve Warrington
AU  - Douglas C. Beshore
TI  - Preclinical to Human Translational Pharmacology of the Novel M<sub>1</sub> Positive Allosteric Modulator MK-7622
AID  - 10.1124/jpet.117.245894
DP  - 2018 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 556--566
VI  - 365
IP  - 3
4099  - http://jpet.aspetjournals.org/content/365/3/556.short
4100  - http://jpet.aspetjournals.org/content/365/3/556.full
SO  - J Pharmacol Exp Ther2018 Jun 01; 365
AB  - The current standard of care for treating Alzheimer’s disease is acetylcholinesterase inhibitors, which nonselectively increase cholinergic signaling by indirectly enhancing activity of nicotinic and muscarinic receptors. These drugs improve cognitive function in patients, but also produce unwanted side effects that limit their efficacy. In an effort to selectively improve cognition and avoid the cholinergic side effects associated with the standard of care, various efforts have been aimed at developing selective M1 muscarinic receptor activators. In this work, we describe the preclinical and clinical pharmacodynamic effects of the M1 muscarinic receptor-positive allosteric modulator, MK-7622. MK-7622 attenuated the cognitive-impairing effects of the muscarinic receptor antagonist scopolamine and altered quantitative electroencephalography (qEEG) in both rhesus macaque and human. For both scopolamine reversal and qEEG, the effective exposures were similar between species. However, across species the minimum effective exposures to attenuate the scopolamine impairment were lower than for qEEG. Additionally, there were differences in the spectral power changes produced by MK-7622 in rhesus versus human. In sum, these results are the first to demonstrate translation of preclinical cognition and target modulation to clinical effects in humans for a selective M1 muscarinic receptor-positive allosteric modulator.