Inhibition of monoamine oxidase B by N-methyl-2-phenylmaleimides.
Based on a recent report that 1-methyl-3-phenylpyrrolyl analogues are moderately potent reversible inhibitors of the enzyme monoamine oxidase B (MAO-B), a series of structurally related N-methyl-2-phenylmaleimidyl analogues has been prepared and evaluated as inhibitors of MAO-B. In general, the maleimides were more potent competitive inhibitors than the corresponding pyrrolyl analogues. N-Methyl-2-phenylmaleimide was found to be the most potent inhibitor with an enzyme-inhibitor dissociation constant (K(i) value) of 3.49 microM, approximately 30-fold more potent than 1-methyl-3-phenylpyrrole (K(i)=118 microM). This difference in activities may be dependent upon the ability of the maleimidyl heterocyclic system to act as a hydrogen bond acceptor. This is in correspondence with literature reports which suggest that hydrogen bond formation is involved in stabilizing inhibitor-MAO-B complexes. Also reported here is a brief kinetic study of the hydrolysis of the N-methyl-2-phenylmaleimidyl analogues in aqueous solution. The findings of the inhibition studies are discussed with reference to the rate and extent of hydrolysis.
Manley-King
Clarina I
CI
Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
Terre'Blanche
Gisella
G
Castagnoli
Neal
N
Bergh
Jacobus J
JJ
Petzer
Jacobus P
JP