Kruse L I, Kaiser C, DeWolf W E, Frazee J S, Garvey E, Hilbert E L, Faulkner W A, Flaim K E, Sawyer J L, Berkowitz B A
J Med Chem. 1986 Dec;29(12):2465-72. doi: 10.1021/jm00162a008.
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.
描述了一些1-(苯基烷基)咪唑-2-硫酮作为多巴胺β-羟化酶(DBH)新型“多底物”抑制剂的合成与表征。这些抑制剂具有类似于酪胺和氧底物的结构特征，稳态动力学表明，它们似乎能结合DBH中的苯乙胺结合位点和活性位点铜原子。一系列在苯环(多巴胺模拟物)和咪唑-2-硫酮基团(氧模拟物)之间引入不同桥链长度的结构类似物，确定了抑制效力的最佳距离以及DBH活性位点中可能的位点间距离。制备了额外的桥连类似物，以确定活性位点的体积耐受性和杂原子取代的影响。
