Yoshida Shinichi, Meyer Oliver G J, Rosen Thomas C, Haufe Günter, Ye Song, Sloan Milton J, Kirk Kenneth L
Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Department of Health and Human Services, Bethesda, Maryland 20892, USA.
J Med Chem. 2004 Mar 25;47(7):1796-806. doi: 10.1021/jm030398k.
Two series of diastereopure phenylcyclopropylamine analogues, 2-fluoro-2-phenylcyclopropylamines and 2-fluoro-2-phenylcyclopropylalkylamines, as well as 2-fluoro-1-phenylcyclopropylamines and 2-fluoro-1-phenylcyclopropylmethylamines, were synthesized in order to study the effects of fluorine substitution on monoamine oxidase inhibition. Inhibitory activity was assayed using commercially available microbial tyramine oxidase. Characterization of tyramine oxidase, carried out prior to the inhibition experiments, confirmed earlier suggestions that this enzyme is a semicarbazide-sensitive copper-containing monoamine oxidase. The most potent competitive inhibitor was trans-2-fluoro-2-phenylcyclopropylamine, which had an IC(50) value 10 times lower than that of the nonfluorinated compound, tranylcypromine. 2-Fluoro-1-phenylcyclopropylmethylamine was found to be a weak noncompetitive inhibitor of tyramine oxidase. The presence of a free amino group, directly bonded to the cyclopropane ring, and a fluorine atom in a relationship cis to the amino group were structural features that increased tyramine oxidase inhibition.
为了研究氟取代对单胺氧化酶抑制作用的影响，合成了两类非对映体纯的苯基环丙胺类似物，即2-氟-2-苯基环丙胺和2-氟-2-苯基环丙基烷基胺，以及2-氟-1-苯基环丙胺和2-氟-1-苯基环丙基甲胺。使用市售的微生物酪胺氧化酶测定抑制活性。在抑制实验之前对酪胺氧化酶进行的表征证实了早期的推测，即该酶是一种对氨基脲敏感的含铜单胺氧化酶。最有效的竞争性抑制剂是反式-2-氟-2-苯基环丙胺，其IC(50)值比非氟化化合物反苯环丙胺低10倍。发现2-氟-1-苯基环丙基甲胺是酪胺氧化酶的一种弱非竞争性抑制剂。直接与环丙烷环相连的游离氨基以及与氨基呈顺式关系的氟原子的存在是增强酪胺氧化酶抑制作用的结构特征。
