Development of VU6019650 : A Potent, Highly Selective, and Systemically Active Orthosteric Antagonist of the M 5 Muscarinic Acetylcholine Receptor for the Treatment of Opioid Use Disorder.

Autor: Garrison AT; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Orsi DL; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Capstick RA; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Whomble D; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Li J; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Carter TR; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Felts AS; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Vinson PN; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Rodriguez AL; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Han A; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Hajari K; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Cho HP; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Teal LB; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Ragland MG; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Ghamari-Langroudi M; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Bubser M; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Chang S; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Schnetz-Boutaud NC; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Boutaud O; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Blobaum AL; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Foster DJ; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Niswender CM; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Conn PJ; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.; Vanderbilt Kennedy Center, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Lindsley CW; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.; Department of Chemistry, Vanderbilt University, Nashville, Tennessee 37232, United States.; Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, Tennessee 37232, United States., Jones CK; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States., Han C; Warren Center for Neuroscience Drug Discovery, Vanderbilt University, Nashville, Tennessee 37232, United States.; Department of Pharmacology, Vanderbilt University, School of Medicine, Nashville, Tennessee 37232, United States.
Jazyk: angličtina
Zdroj: Journal of medicinal chemistry [J Med Chem] 2022 Apr 28; Vol. 65 (8), pp. 6273-6286. Date of Electronic Publication: 2022 Apr 13.
DOI: 10.1021/acs.jmedchem.2c00192
Abstrakt: The muscarinic acetylcholine receptor (mAChR) subtype 5 (M 5 ) represents a novel potential target for the treatment of multiple addictive disorders, including opioid use disorder. Through chemical optimization of several functional high-throughput screening hits, VU6019650 ( 27b ) was identified as a novel M 5 orthosteric antagonist with high potency (human M 5 IC 50 = 36 nM), M 5 subtype selectivity (>100-fold selectivity against human M 1-4 ) and favorable physicochemical properties for systemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies, 27b blocked the nonselective muscarinic agonist oxotremorine-M-induced increases in neuronal firing rates of midbrain dopamine neurons in the ventral tegmental area, a part of the mesolimbic dopaminergic reward circuitry. Moreover, 27b also inhibited oxycodone self-administration in male Sprague-Dawley rats within a dose range that did not impair general motor output.
Databáze: MEDLINE
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