Stereospecificity of the effect of flupenthixol isomers on substrate inhibition of brain tyrosine hydroxylase

Abstract

Stereospecificity of the effect of neuroleptics on substrate inhibition of isolated brain tyroxine hydroxylase is shown. Flupentixole cis-isomer eliminates substrate inhibition of the enzyme. The effect is concentration-dependent and is well marked within the tyrosine concentration range 10-6-10-4 M. Flupentixole trans-isomer in the same concentrations has no effect on substrate inhibition of tyrosine hydroxylase. In the presence of cis-flupentixole, the reaction rate plotted against tyrosine concentration is a hyperbole with a plateau at 160-360 microM tyrosine. In the presence of trans-isomer, as in the control sample, the relationships between the reaction rate and tyrosine concentration are depicted by a curve with a maximum (at 110-140 microM tyrosine). Like ftorphenazine, flupentixole isomer fails to eliminate the inhibitory action of alpha-methyl paratyrosine, which indicates the interaction of neuroleptics with the tyrosine-binding site of the enzyme molecules in the noncatalytic centrer. It is suggested that the interaction of the neuroleptics with the regulatory area of tyrosine hydroxylase might by important in the molecular mechanism of their action.