6gy1 | pdb_00006gy1
rat COMT in complex with inhibitor
Structural highlights
FunctionCOMT_RAT Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones. Also shortens the biological half-lives of certain neuroactive drugs, like L-DOPA, alpha-methyl DOPA and isoproterenol. Publication Abstract from PubMedA series of 8-hydroxy quinolines were identified as potent inhibitors of catechol O-methyltransferase (COMT) with selectivity for the membrane-bound form of the enzyme. Small substituents at the 7-position of the quinoline were found to increase metabolic stability without sacrificing potency. Compounds with good pharmacokinetics and brain penetration were identified and demonstrated in vivo modulation of domamine metabolites in the brain. An X-ray co-crystal structure of compound 21 in the S-COMT active site shows chelation of the active site magnesium similar to catechol-based inhibitors. These compounds should prove useful for treatment of many neurological and psychiatric conditions associated with compromised cortical dopamine signaling. Optimization of 8-Hydroxyquinolines as Inhibitors of Catechol O-Methyltransferase.,Buchler I, Akuma D, Au VQ, Carr G, de Leon P, DePasquale M, Ernst G, Huang Y, Kimos M, Kolobova A, Poslusney MS, Wei H, Swinnen D, Montel F, Moureau F, Jigorel E, Schulze MS, Wood M, Barrow JC J Med Chem. 2018 Oct 1. doi: 10.1021/acs.jmedchem.8b01126. PMID:30272964[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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