1-(THIENYLALKYL)IMIDAZOLE-2(3H)-THIONES AS POTENT COMPETITIVE INHIBITORS OF DOPAMINE BETA-HYDROXYLASE

1-(2-Thienylalkyflimidazole-2(3H)-thiones (5a—k) are competitive inhibitors of dopamine 0-hydroxylase (DBH) and demonstrate the utility of thiophene in the design of potent competitive inhibitors of this enzyme. The structure—activity relationships for these compounds are discussed and compared with those of 1-phenylalkyl-imidazole-2(3H)-thiones (1). With the aid of molecular modeling, an idealized active-site conformer is proposed and an explanation for the difference in activity between the phenyl (1) and thienyl (5) DBH inhibitors is presented. The difference in activity is consistent with our proposal that thiophene may not always be a bioisostere for phenyl. The inhibitor of most interest, 1-[2-(2-thienyl)ethyl] imidazole-2 (3H)-thione (5g), was selected for study in the spontaneously hypertensive rat. The changes in dopamine and norepinephrine levels that resulted from oral administration of 5g correlated with the reduction of blood pressure. © 1990, American Chemical Society. All rights reserved.