Multisubstrate inhibitors of dopamine .beta.-hydroxylase. 1. Some 1-phenyl and 1-phenyl-bridged derivatives of imidazole-2-thione

The synthesis and characterization of some 1-(phenylalkyl)imidazole-2-thiones as a novel class of "multisubstrate" inhibitors of dopamine beta-hydroxylase (DBH) are described. These inhibitors incorporate structural features that resemble both tyramine and oxygen substrates, and as evidenc...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1986-12, Vol.29 (12), p.2465-2472
Main Authors: Kruse, Lawrence I, Kaiser, Carl, DeWolf, Walter E, Frazee, James S, Garvey, Eleanor, Hilbert, Eileen L, Faulkner, Wayne A, Flaim, Kathryn E, Sawyer, John L, Berkowitz, Barry A
Format: Article
Language:English
Subjects:
Animals
Cattle
Dopamine beta-Hydroxylase - antagonists & inhibitors
Imidazoles - chemical synthesis
Imidazoles - pharmacology
Indicators and Reagents
Kinetics
Magnetic Resonance Spectroscopy
Spectrophotometry, Infrared
Structure-Activity Relationship
Thiones - chemical synthesis
Thiones - pharmacology
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Summary:The synthesis and characterization of some 1-(phenylalkyl)imidazole-2-thiones as a novel class of "multisubstrate" inhibitors of dopamine beta-hydroxylase (DBH) are described. These inhibitors incorporate structural features that resemble both tyramine and oxygen substrates, and as evidenced by steady-state kinetics, they appear to bind both the phenethylamine binding site and the active site copper atom(s) in DBH. A series of structural congeners that incorporate different bridging chain lengths between the phenyl ring (dopamine mimic) and the imidazole-2-thione group (oxygen mimic) define the optimum distance for inhibitory potency and the likely intersite distance in the DBH active site. Additional bridging analogues were prepared to determine the active site bulk tolerance and the effects of heteroatom replacement.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00162a008