Fluorinated phenylcyclopropylamines. 1. Synthesis and effect of fluorine substitution at the cyclopropane ring on inhibition of microbial tyramine oxidase.
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.
Yoshida
Shinichi
S
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.
Meyer
Oliver G J
OG
Rosen
Thomas C
TC
Haufe
Günter
G
Ye
Song
S
Sloan
Milton J
MJ
Kirk
Kenneth L
KL
D001665:Binding Sites; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry
C484867:2-fluoro-2-phenylcyclopropylamine; D003521:Cyclopropanes; D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; D008995:Monoamine Oxidase