6gy1

Publication Abstract from PubMed

A 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.