Role of substrate lipophilicity on the N-demethylation and type I binding of 3-O-alkylmorphine analogues.
A series of 3-O-alkylmorphine analogues was synthesized to determine if there was a good correlation between the rate of metabolism, type I binding affinity, and lipid solubility. The data indicate that the Km for the N-demethylation declines with increasing chain length from C1 to C9, while for increasing chain length the Vmax for the N-demethylation increases to a maximum of 15.20 nmol min-1 (mg of protein)-1 for the butyl analogue (C4) and then slowly declines with analogues with chain lengths greater than butyl (C4). The decyl (C10) and dodecyl (C12) analogues showed no activity. There was a good correlation between the lipophilicity and Km values, except for codeine and the C10 and C12 analogues. The type I binding dissociation constants (Ks) also decreased with increasing alkyl chain length with an excellent correlation between the Ks and log P. The ODmax did not change with increasing the chain length of the analogues. Our data suggest that in male rat hepatic microsomes the catalytic site for N-demethylation and the site for type I binding in this series of compounds are similar but distinct.
D000478:Alkylation; D000818:Animals; D007700:Kinetics; D008297:Male; D008862:Microsomes, Liver / Q000201:enzymology*; D009020:Morphine / Q000378:metabolism / Q000494:pharmacology; D009022:Morphine Derivatives; D010089:Oxidoreductases, N-Demethylating / Q000378:metabolism*; D051381:Rats; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D009022:Morphine Derivatives; D009020:Morphine; D010089:Oxidoreductases, N-Demethylating; C021806:morphine-N-demethylase