Structure-activity relationships in the inhibition of monoamine oxidase B by 1-methyl-3-phenylpyrroles.
1-Methyl-3-phenyl-3-pyrrolines are structural analogues of the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and like MPTP are selective substrates of monoamine oxidase B (MAO-B). As part of an ongoing investigation into the substrate properties of various 1-methyl-3-phenyl-3-pyrrolinyl derivatives, it is shown in the present study that their respective MAO-B catalyzed oxidation products act as reversible competitive inhibitors of the enzyme. The most potent inhibitor among the oxidation products considered was 1-methyl-3-(4-trifluoromethylphenyl)pyrrole with an enzyme-inhibitor dissociation constant (K(i) value) of 1.30 microM. The least potent inhibitor was found to be 1-methyl-3-phenylpyrrole with a K(i) value of 118 microM. The results of an SAR study established that the potency of MAO-B inhibition by the 1-methyl-3-phenylpyrrolyl derivatives examined here is dependent on the Taft steric parameter (E(s)) and Swain-Lupton electronic constant (F) of the substituents attached to C-4 of the phenyl ring. Electron-withdrawing substituents with a large degree of steric bulkiness appear to enhance inhibition potency. Potency was also found to vary with the substituents at C-3, again with E(s) and F being the principal substituent descriptors.
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Modupe O
MO
Ogunrombi
Sarel F
SF
Malan
Gisella
G
Terre'blanche
Neal
N
Castagnoli
Jacobus J
JJ
Bergh
Jacobus P
JP
Petzer
D000818:Animals; D002384:Catalysis; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010215:Papio; D011758:Pyrroles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship
D008996:Monoamine Oxidase Inhibitors; D011758:Pyrroles; D008995:Monoamine Oxidase