期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 65, 期 8, 页码 6273-6286出版社
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.2c00192
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资金
- Ancora Innovation, LLC
- William K. Warren Family and Foundation
- Vanderbilt Institute of Chemical Biology
- Vanderbilt Ingram Cancer Center [P30 CA68485]
The muscarinic acetylcholine receptor subtype 5 (M5) is a potential target for treating addictive disorders. The compound VU6019650 (27b) has been identified as a potent M5 antagonist and has shown potential in preclinical addiction models.
The muscarinic acetylcholine receptor (mAChR)subtype 5 (M5) represents a novel potential target for thetreatment of multiple addictive disorders, including opioid usedisorder. Through chemical optimization of several functionalhigh-throughput screening hits,VU6019650(27b) was identifiedas a novel M5orthosteric antagonist with high potency (human M5IC50= 36 nM), M5subtype selectivity (>100-fold selectivity againsthuman M1???4) and favorable physicochemical properties forsystemic dosing in preclinical addiction models. In acute brain slice electrophysiology studies,27bblocked the nonselectivemuscarinic agonist oxotremorine-M-induced increases in neuronalfiring rates of midbrain dopamine neurons in the ventraltegmental area, a part of the mesolimbic dopaminergic reward circuitry. Moreover,27balso inhibited oxycodone self-administrationin male Sprague-Dawley rats within a dose range that did not impair general motor output.
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