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.
Copyright 2001 Academic Press.
Publication types
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Amino Acid Sequence
-
Catalysis / drug effects
-
Coumarins / chemical synthesis
-
Coumarins / chemistry*
-
Coumarins / metabolism*
-
Cytochrome P-450 CYP2D6 / chemistry
-
Cytochrome P-450 CYP2D6 / isolation & purification
-
Cytochrome P-450 CYP2D6 / metabolism*
-
Cytochrome P-450 CYP2D6 Inhibitors
-
Enzyme Inhibitors / pharmacology
-
Fluorescent Dyes / chemical synthesis
-
Fluorescent Dyes / chemistry*
-
Fluorescent Dyes / metabolism*
-
Humans
-
Kinetics
-
Microsomes, Liver / drug effects
-
Microsomes, Liver / enzymology
-
Microsomes, Liver / metabolism
-
Molecular Sequence Data
-
Quinidine / pharmacology
-
Recombinant Proteins / antagonists & inhibitors
-
Recombinant Proteins / chemistry
-
Recombinant Proteins / isolation & purification
-
Recombinant Proteins / metabolism
-
Substrate Specificity
Substances
-
Coumarins
-
Cytochrome P-450 CYP2D6 Inhibitors
-
Enzyme Inhibitors
-
Fluorescent Dyes
-
Recombinant Proteins
-
coumarin
-
Cytochrome P-450 CYP2D6
-
Quinidine