The molecular pharmacology of L-deprenyl

Abstract

L-Deprenyl, the selective inhibitor of monoamine oxidase type B (MAO-B) has gained wide acceptance as a useful form of adjunct therapeutic drug in the treatment of Parkinson's disease. This review summarizes the molecular pharmacology of L-deprenyl, and the advances in our understanding of its possible mode of action in Parkinson's disease. l-Deprenyl belongs to the class of enzyme-activated irreversible inhibitors also described as ‘suicide’ inhibitors, because the compound acts as a substrate for the target enzyme, whose action on the compound results in irreversible inhibition. l-Deprenyl first of all forms a noncovalent complex with MAO as an initial, reversible step. The subsequent interaction of l-deprenyl with MAO leads to a reduction of the enzyme-bound flavine-adenine dinucleotide (FAD), and concomitant oxidation of the inhibitor. This oxidized inhibitor then reacts with FAD at the N-5-position in a covalent manner. The observed in vitro selectivity of L-deprenyl for MAO-B may be accounted for by differences in the affinities of the two MAO subtypes for reversible interaction with L-deprenyl, differences in the rates of reaction within the noncovalent complexes to form the irreversibly inhibited adduct, or a combination of both these factors. However, if selective inhibition is to be maintained in vivo, correct dosage schedules are critically important, since all selective MAO inhibitors described up to now lack selectivity at high doses. In experimental animals L-deprenyl is protective against the damaging effects of several neurotoxins, including the dopaminergic agents 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine (6-OHDA) and the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). Beside MAO-B inhibition, which above all explains the prevention of neurotoxic action of MPTP by preventing its metabolism. L-deprenyl appears to exhibit other mechanisms of action which are independent of its action on MAO-B.