Inhibition of monoamine oxidase by analogues of amiloride.
Amiloride analogues with nonaromatic substituents on the 5-amino group or different substituents on carbon-6 of the pyrazine ring were tested as inhibitors of monoamine oxidase A and B in rat brain homogenate. The inhibition was competitive and reversible. 5-(N,N-Tetramethylene)amiloride protected the A type in the homogenate against irreversible inhibition by clorgyline. A reciprocal relation was found to exist between inhibitory constants of 5-N-substituted amiloride analogues for monoamine oxidase A and the ratio of overflows of endogenous noradrenaline and 3,4-dihydroxyphenylethylene glycol from the isolated rat tail artery incubated in the presence of a 50 microM concentration of the analogue, when the tissue was exposed to 10 microM tyramine. The 5-amino group appeared to be essential for inhibition of the A but not of the B type. Bell-shaped relations between inhibitory constants of 5-(N-alkyl)- and 5-(N,N-dialkyl)-substituted analogues and lengths of alkyl chains were different for each type. The presence of a methyl group in the alpha-position of the chain increased substantially the inhibitory constant for the A type. Halogen atoms as substituents on carbon-6 increased inhibitory constants for both types of the enzyme in the sequence: I less than Br less than Cl less than F. These findings are consistent with the existence of hydrophobic binding sites of restricted dimensions in both types of the enzyme.
Palatý
V
V
Department of Anatomy, University of British Columbia, Vancouver, Canada.
Cragoe
E J
EJ
D000320:Adrenergic Fibers / Q000201:enzymology; D000584:Amiloride / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000294:innervation; D001921:Brain / Q000201:enzymology; D003010:Clorgyline / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D008996:Monoamine Oxidase Inhibitors; D051381:Rats; D013329:Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D000584:Amiloride; D003010:Clorgyline