title: Coumarin substrates for cytochrome P450 2D6 fluorescence assays.
abstract: A set of nine 4-aminomethyl-7-alkoxycoumarin derivatives was synthesized and characterized as substrates for O-dealkylation by recombinant cytochrome P450 2D6, a major human enzyme involved in drug metabolism. Enzymatic O-dealkylation yields 7-hydroxycoumarins, which have useful fluorescence properties. The substrates, which differed in substitution at the amino and 7-hydroxy positions, varied in terms of catalytic efficiency of O-dealkylation and in their selectivity as substrates for cytochrome P450 2D6 in human liver microsomes. Several of the compounds are useful as cytochrome P450 2D6 substrates in single-phase, rapid-throughput assays.
authors.affiliation: Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
authors.forename: K
authors.initials: K
authors.lastname: Nakamura
authors.forename: I H
authors.initials: IH
authors.lastname: Hanna
authors.forename: H
authors.initials: H
authors.lastname: Cai
authors.forename: Y
authors.initials: Y
authors.lastname: Nishimura
authors.forename: K M
authors.initials: KM
authors.lastname: Williams
authors.forename: F P
authors.initials: FP
authors.lastname: Guengerich
mesh_terms: D000595:Amino Acid Sequence; D002384:Catalysis / Q000187:drug effects; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D019389:Cytochrome P-450 CYP2D6 / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism*; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008969:Molecular Sequence Data; D011802:Quinidine / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism; D013379:Substrate Specificity
chemical_list: D003374:Coumarins; D065690:Cytochrome P-450 CYP2D6 Inhibitors; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D011994:Recombinant Proteins; C030123:coumarin; D019389:Cytochrome P-450 CYP2D6; D011802:Quinidine