Preclinical to Human Translational Pharmacology of the Novel M 1 Positive Allosteric Modulator MK-7622

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 365; no. 3; pp. 556 - 566
• Main Authors: Uslaner, Jason M, Kuduk, Scott D, Wittmann, Marion, Lange, Henry S, Fox, Steven V, Min, Chris, Pajkovic, Natasa, Harris, Dawn, Cilissen, Caroline, Mahon, Chantal, Mostoller, Kate, Warrington, Steve, Beshore, Douglas C
• Format: Journal Article
• Language: English
• Published: United States 01.06.2018
• Subjects: orexins
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.117.245894

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. Herein 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 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 vs. human. In sum, these results are the first to demonstrate translation of preclinical cognition and target modulation to clinical effects in man for a selective M1 muscarinic receptor positive allosteric modulator.