Coumarin substrates for cytochrome P450 2D6 fluorescence assays.
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.
Nakamura
K
K
Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.
Hanna
I H
IH
Cai
H
H
Nishimura
Y
Y
Williams
K M
KM
Guengerich
F P
FP
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
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