Oxidation of Analogs of l‐Methyl‐4‐Phenyl‐1,2,3,6‐Tetrahydropyridine by Monoamine Oxidases A and B and the Inhibition of Monoamine Oxidases by the Oxidation Products

Abstract: Twenty analogs of l‐methyl‐4‐phenyl‐l,2,3,6‐tet‐rahydropyridine (MPTP) were tested for their capacity to be xidized by pure monoamine oxidase‐A (MAO‐A) prepared from human placenta and pure monoamine oxidase‐B (MAO‐B) prepared from beef liver. Several of the MPTP analogs were very good substrates for MAO‐A, for MAO‐B, or for both and had low K_m values and high turnover numbers. These values were similar to or even better than those of kynuramine and benzylamine, good substrates for MAO‐A and MAO‐B, respectively. MPTP had relatively low K_m values for oxidation by both MAO‐A and MAO‐B. In contrast, the turnover number for MPTP oxidation by MAO‐B was considerably higher than the value for MAO‐A. The corresponding pyridinium species of MPTP and several of the MPTP analogs inhibited MAO‐A competitively with K_i values at micromolar concentrations; in contrast the pyridinium species inhibited MAO‐B competitively at considerably higher concentrations (i.e., 100 μM or greater K_i values). The data provide information concerning the structural requirements for the oxidation of tetrahydropyridines by MAO‐A and MAO‐B and the inhibition of these enzymes by pyridini‐ums