DRAMATIC SPECIES-DIFFERENCES IN THE SUSCEPTIBILITY OF MONOAMINE-OXIDASE-B TO A GROUP OF POWERFUL INHIBITORS

Oxadiazolones and oxadiazolethiones are potent, reversible competitive inhibitors of MAO B in rat brain mitochondria. We have compared the K-i values of six of these inhibitors toward MAO B from rat, human and beef liver mitochondria, using benzylamine as substrate. Unexpectedly, their inhibitory potency Varies by 3 to 4 orders of magnitude between rat and beef liver MAO B, whereas the inhibition of the rat and human liver enzymes is quite similar. Examples are 5-(4-benzyl-oxyphenyl)-3-(2-cyano-ethyl)-1,3,4-oxadiazole-2(3H)- thione, with K-i at 30 degrees of 0.5 nM for rat, 0.8 nM for human, and 1,830 nM for beef fiver mitochondria and 5-(4-benzyloxyphenyl)-3-(2-hydroxyethyl)-1,3,4-oxadiazol-2(3H)- one with K-i values of 1.2, 1.1 and 1,320 nM for MAO B from these three sources. Since solubilized and membrane-bound enzymes had similar sensitivities to the inhibitors, the differences seen must arise from differences in the amino acid sequences of the three enzymes. (C) 1995 Academic Press, Inc.