Probing the active sites of monoamine oxidase A and B with 1,4-disubstituted tetrahydropyridine substrates and inactivators.
As part of our efforts to characterize more fully the structural features of the monoamine oxidase (MAO) A and B active sites, we have examined the substrate and inhibitor properties of several 1-methyl- and 1-cyclopropyl-4-aryl-1,2,3,6-tetrahydropyridine derivatives with the human placental A and beef liver B forms of the enzyme. We find that the 4-(2-phenylphenyl) analog 23 exhibits a high activity and selectivity for MAO-A while the 4-(3-phenylphenyl) analog 22 shows activity only with MAO-B. Selectivities similar to those of the N-methyl series are observed with a series of N-cyclopropyl mechanism based inactivators. These results support a topological analysis which attempts to identify steric factors related to the reported substrate and inhibitor selectivities of these two flavoproteins and provide a better definition of the size of the active sites of the two enzymes.
Palmer
S L
SL
Department of Chemistry, Virginia Polytechnic Institute and State University, Blacksburg 24061-0212, USA.
Mabic
S
S
Castagnoli
N
N
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008956:Models, Chemical; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D010920:Placenta / Q000201:enzymology; D011725:Pyridines / Q000737:chemistry* / Q000378:metabolism
D011725:Pyridines; D008995:Monoamine Oxidase