Inhibition of dihydropteridine reductase from human liver and rat striatal synaptosomes by apomorphine and its analogs.
Dihydropteridine reductase from human liver and rat striatal synaptosomes is noncompetitively inhibited by apomorphine and its analogs. The Ki or I50 values are in the range of 0.6 to 2.9 microM for R-(-)-apomorphine, R-(-)-and S-(+)-2, 10, 11-trihydroxyaporphine, R-(-)-norapomorphine, R-(-)-N-hydroxyethylnorapomorphine, R-(-)-2,10,11-trihydroxy-N-n-propylnoraporphine, R-(-)- and S-(+)-N-n-propylnorapomorphine, and R-(-)-N-chloroethylnorapomorphine; and 13 to 151 microM for R-(-)-2,11-dihydroxy- 10-methoxyaporphine, R-(-)-apocodeine, and S-(+)-bulbocapnine. Structure-activity studies reveal that 10,11-dihydroxy substitution of the D ring of apomorphine is required for the inhibitory effectiveness of these aporphines. Methylation of the 10-hydroxy group reduces, whereas the 2-hydroxyl substitution of the A ring enhances, their inhibitory potency. N-Alkylation variably affects the inhibitory potency of aporphines. In addition, S-(+)-enantiomers of aporphines and dopaminergic antagonists are equally potent as inhibitors of this enzyme, as compared to the corresponding R-(-)-enantiomers and other aporphine agonists. Haloperidol (0.1 to 10 microM) failed to reverse the enzyme inhibitory effectiveness of apomorphine when it was incubated with intact rat striatal synaptosomes prior to or after the addition of apomorphine (0.5 to 1 microM). These results suggest that the inhibitory effects of apomorphine and its analogs against this enzyme are not mediated by their stimulation of dopamine autoreceptors. Since dihydropteridine reductase is required in vivo for the hydroxylation of tyrosine, the inhibition of this enzyme by apomorphine may represent one of several mechanisms by which apomorphine inhibits catecholamine synthesis.
D000818:Animals; D001058:Apomorphine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D003342:Corpus Striatum / Q000201:enzymology*; D004093:Dihydropteridine Reductase / Q000037:antagonists & inhibitors* / Q000302:isolation & purification / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology*; D008297:Male; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D004093:Dihydropteridine Reductase; D009247:NADH, NADPH Oxidoreductases; D001058:Apomorphine