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

Abstract

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.

Three-Dimensional Common-Feature Hypotheses for Octopamine Agonist 1-Arylimidazolidine-2-Thiones

“…All compounds were prepared using published methods. 1-Arylimidazole-2(3H)-thiones (AIHTs) were prepared by the condensation of the corresponding arylisothiocyanates with aminoacetaldehyde dimethyl acetal followed by acid-catalized cyclization of the intermediate N-arylthioureas [8]. 1-Arylimidazolidine-2-thiones (AITs) were synthesized by the cyclization of monoethanolamine hydrogen sulfate with arylisothiocyanates in the presence of sodium hydroxide as described in the previous report [9].…”

Multisubstrate adduct inhibitors: Drug design and biological tools

“…Dopamine -hydroxylase (DH; EC 1.14.17.1) is a tetrameric, copper containing, mixed-function oxidase that catalyzes benzylic hydroxylation of dopamine to (R)-norepinephrine 28 . In this first study, a phenyl or 4-oxygenated phenyl group was used as a mimic of the dopamine catecholic nucleus for recognition by the aromatic binding site of the enzyme.…”

“…In this first study, a phenyl or 4-oxygenated phenyl group was used as a mimic of the dopamine catecholic nucleus for recognition by the aromatic binding site of the enzyme. Synthesis and testing of a first panel of inhibitors was undertaken in order to optimize the space between the aryl system and the dopamine catechol mimic 28 . Compound 6 (X = OH, Y = CH 2 , IC 50 = 2.6 M, K i = 0.00549 M at pH 4.5, 0.344 M at pH 6.6) binds DH approximately 10 5 -fold more tightly than the tyramine (K m = 5.65 mM) and appears more potent than furasic acid, the inhibitor which underwent clinical trials.…”

“…The compounds 7a-c and 8, 9, 10 were tested for inhibition of DH in vitro and in vivo (Table 2), with reference data for three 1-(arylmethyl)-imidazole-2-thiones [28][29][30] and a standard DH inhibitor (furasic acid) 32 . Compounds 7a-c were potent as DH inhibitors in vitro (IC 50 ≈ 10 −4 M) and even more potent in vivo.…”

Synthesis and biological evaluation ofS-[11C]methylated mercaptoimidazole piperazinyl derivatives as potential radioligands for imaging 5-HT1Areceptors by positron emission tomography (PET)

“…23 The synthesis of the labelling precursor 3 was accomplished in 50% yield by cyclization of a diethyl acetal derivative (2) with potassium thiocyanate under acidic conditions, which is a common method for the synthesis of 2-mercaptoimidazoles (Scheme 3). 24,25 Amino acetal 2 has been obtained by alkylation of compound 1 with bromoacetaldehyde diethyl acetal. The reaction was performed using an excess of primary amine 1 to avoid overalkylation.…”