Irreversible Inhibition of Rat Liver Mitochondrial MAO A and MAO B by Enantiomers of Deprenyl and α-Methylpargyline

Abstract

Using rat liver mitochondrial monoamine oxidase (MAO) A and MAO B, the possible influence of stereochemical factors upon the irreversible inhibition by propargylamine derivatives has been studied using the enantiomers of deprenyl and of alpha-methylpargyline. Whether studying the inhibition of MAO A or MAO B, little difference was found among enantiomeric pairs in the first-order rate constant (k2) for formation of the enzyme inhibitor adduct. Similarly, and with the exception of (S)-D-(+)-deprenyl (k2 = 0 or an extremely low value at MAO A), the computed value of k2 for the individual enantiomers showed little variation between MAO A and MAO B. These results suggest that inhibitor selectivity towards a particular form of the enzyme is determined predominantly at the competitive phase of the inhibition.

Design, Synthesis, and Biological Activities of Pyrrolylethanoneamine Derivatives, a Novel Class of Monoamine Oxidases Inhibitors

“…In general, R isomers (18,20,22) were more active than the parent racemates (3, 4, 8) and 2-10 times more potent than the S counterparts (19,21,23). In particular, compound 18 showed the highest potency and selectivity (K i (MAO-A) ) 0.0035 µM, K i (MAO-B) ) 700 µM, and A-selectivity ) 200000) among all test derivatives.…”

“…Because of the well-known stereoselectivity of enantiomeric chiral MAOIs such as selegiline (SEL) 21 and oxazolidinones, 22 we decided to resolve a number of potent racemates (3, 4, 8) and aminoethanols 13, 14 to determine the impact of chirality in biological efficacy within this novel class of MAOIs. Single enantiomers 18-27 were obtained by semipreparative HPLC of the racemic mixtures on a polysaccharide-based chiral stationary phase (CSP) 23 (Chiralpak AD) (the reader is referred to the Supporting Information for details of the separation methods).…”