Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622
| العنوان: | Preclinical to Human Translational Pharmacology of the Novel M1 Positive Allosteric Modulator MK-7622 |
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| المؤلفون: | Steven V. Fox, Kate Mostoller, Steve Warrington, Chris Min, Caroline Cilissen, Marion Wittmann, Douglas C. Beshore, Dawn Harris, Henry S. Lange, Natasa Pajkovic, Jason M. Uslaner, Chantal Mahon, Scott D. Kuduk |
| المصدر: | Journal of Pharmacology and Experimental Therapeutics. 365:556-566 |
| بيانات النشر: | American Society for Pharmacology & Experimental Therapeutics (ASPET), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Pharmacology, Allosteric modulator, business.industry, Antagonist, Quantitative electroencephalography, Acetylcholinesterase, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Nicotinic agonist, chemistry, Muscarinic acetylcholine receptor, Molecular Medicine, Medicine, Cholinergic, Receptor, business, 030217 neurology & neurosurgery |
| الوصف: | 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. |
| تدمد: | 1521-0103 0022-3565 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_________::21df26582717ec1aa725263055cd8e11 https://doi.org/10.1124/jpet.117.245894 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi...........21df26582717ec1aa725263055cd8e11 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15210103 00223565 |
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