Enzyme-activated irreversible inhibitors of monoamine oxidase: phenylallylamine structure-activity relationships.
Seventeen 2-aryl-3-haloallylamine derivatives were prepared and evaluated as inhibitors of monoamine oxidase (MAO, EC 1.4.3.4). The synthesis of these compounds was achieved from either alpha-methylstyrene or ring-substituted phenylacetic acid derivatives. With one exception, these 2-arylallylamines were found to be enzyme-activated, irreversible inhibitors of MAO. The most potent inhibitors were ring-substituted derivatives of (E)-2-phenyl-3-fluoroallylamine with IC50 values ranging from 10(-6) to 10(-8) M. Selectivity for the A and B form of MAO was found to depend on the nature of aromatic ring substitution. In general, hydroxyl substitution favored the inactivation of the A form of MAO, while very selective B inhibitors were obtained when the aromatic ring was substituted with a 4-methoxy group. (E)-2-(4-Methoxyphenyl)-3-fluoroallylamine and (E)-2-(3,4-dimethoxyphenyl)-3-fluoroallylamine proved to be in vitro as selective for the B form of MAO as deprenyl.
D000499:Allylamine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology; D000588:Amines / Q000138:chemical synthesis*; D000818:Animals; D001921:Brain / Q000201:enzymology; D007527:Isoenzymes / Q000037:antagonists & inhibitors*; D008297:Male; D051379:Mice; D008928:Mitochondria / Q000201:enzymology; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis*; D009206:Myocardium / Q000201:enzymology; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013329:Structure-Activity Relationship; D013997:Time Factors; D014961:X-Ray Diffraction
D000588:Amines; D007527:Isoenzymes; D008996:Monoamine Oxidase Inhibitors; D010627:Phenethylamines; C029261:phenethylamine; D012701:Serotonin; D000499:Allylamine; D008995:Monoamine Oxidase