Conformational preferences of dopamine analogues for inhibition of norepinephrine N-methyltransferase. Conformationally defined adrenergic agents.
A series of analogues of dopamine (DA) with varying degrees of conformational flexibility have been examined as potential substrates or competitive inhibitors of the enzyme norepinephrine N-methyltransferase (NMT). A conformationally defined (rigid) analogue of the fully extended conformation of DA, 2-amino-6,7-dihydroxybenzonorbornene hydrobromide (3; 6,7-D2HX) proved to be a better substrate than the non-catechol parent 2-aminobenzonorbornene (4; 2HX). However, analogues 3 and 4 displayed equivalent competitive inhibitory activity toward phenylethanolamine (PEA). Neither 6,7-ADTN (5), a DA analogue in the 2-aminotetralin (2AT) system, nor 6,7-DTHIQ (7), a DA analogue in the tetrahydroisoquinoline (THIQ) system, showed substrate activity; 6,7-ADTN was a poorer competitive inhibitor than the parent 2AT but 6,7-DTHIQ was a better competitive inhibitor than its parent, THIQ (8). A tricyclic conformationally defined analogue 9 of 6,7-ADTN was devoid of either substrate or inhibitory activity. From these results it may be concluded that a fully extended side chain conformation is required for NMT substrate activity, and the better substrate activity for 6,7-D2HX compared to 4 is consistent with a proper catechol orientation for interaction with the norepinephrine (NE) binding site of NMT.
D000311:Adrenal Glands / Q000201:enzymology; D000818:Animals; D002417:Cattle; D004298:Dopamine / Q000494:pharmacology*; D007700:Kinetics; D008968:Molecular Conformation; D010625:Phenylethanolamine N-Methyltransferase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
D010625:Phenylethanolamine N-Methyltransferase; D004298:Dopamine