INHIBITION OF DOPAMINE -HYDROXYLASE BY AROMATIC AND ALKYL THIOUREAS

¹ Central Nervous System Research, The Upjohn Company, Kalsmazoo, Michigan

Severall aromatic and alkyl thioureas were effective inhibitors of a purified bovine adrenal dopamine -hydroxylase preparation. Inhibition of the enzyme by U-10,157 (1, 1-dimethyl-3-phenyl-2-thiourea) was competitive with the substrate after a 5-minute preincubation of inhibitor with the enzyme. Increased substrate concentration did not overcome the inhibition with U-10,157 after 15-minute preincubation. Seven of the 21 thioureas which demonstrated in vitro enzyme inhibition were administered i.p. to mice at 200 or 100 mg/kg. Only two of the inhibitors failed to decrease mouse brain norepinephrine. The effects of the inhibitors upon the dopamine content of mouse brain varied greatly, but dopamine levels were generally elevated consistent with inhibition of brain dopamine -hydroxylase in vivo. Maximum depletion of rat brain norepinephrine reached 40% of control four to seven hours after U-10,157, 200 mg/kg. A chelating mechanism for in vitro and in vivo enzyme inhibition is briefly discussed.