A model for the selective mode of action of the irreversible monoamine oxidase inhibitors clorgyline and deprenyl, based on studies of their ability to activate a Ca2+-Mg2+ ATPase in defined lipid environments

Abstract

Clorgyline and deprenyl activated the pure Ca2+-Mg2+ ATPase from rabbit muscle sarcoplasmic reticulum when it was in a defined lipid environment of either dimyristoyl lecithin or dipalmitoyl lecithin, apparently by fluidizing the phospholipid that surrounds the protein (the phospholipid annulus). Activation was only significant at temperatures when the annulus placed rigid constraints upon the protein. There was a two order of magnitude difference in the concentration at which the drugs achieved their effect which is thought to be related to their abilities to perturb the phospholipid annulus since it could not be attributed simply to the small differences in their partition coefficients. Clorgyline, which was more potent than deprenyl at effecting fluidization of the phospholipid annulus of the Ca2+-Mg2+ ATPase in the defined lipid environments, activated species ‘B’ monoamine oxidase at concentrations at which it began to inhibit the species ‘A’ enzyme. Deprenyl did not activate the species ‘A’ enzyme at any concentration tested. It is suggested that, in tissues where there are multiple forms of mitochondrial monoamine oxidase, the selective action of clorgyline and deprenyl arises from a modification of the single inhibitor binding site on a protein species to yield species ‘A’ enzyme and species ‘B’ enzyme. One form of this modification to give the species ‘A’ monoamine oxidase would be a masking of the inhibitor binding site by lipid such that it could be readily penetrated by clorgyline but less readily so by deprenyl. The other form of the modification would yield the species ‘B’ enzyme, which like the ‘chaotrope-treated’ enzyme and presumably ‘nascent’ monoamine oxidase, would expose the inhibitor binding site to the aqueous environment in which deprenyl would be the more efficacious inhibitor.