Interaction of tetrahydrostilbazoles with monoamine oxidase A and B

• Published in: Journal of medicinal chemistry Vol. 37; no. 1; pp. 151 - 157
• Main Authors: Sablin, Sergey O, Krueger, Matthew J, Singer, Thomas P, Bachurin, Sergey O, Khare, Anil B, Efange, Simon M. N, Tkachenko, Sergey E
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 01.01.1994
• Subjects: 1-Methyl-4-phenylpyridinium - analogs & derivatives; Binding Sites; Bioconversions. Hemisynthesis; Biological and medical sciences; Biotechnology; Chemical Phenomena; Chemistry, Physical; Fundamental and applied biological sciences. Psychology; Isoenzymes - metabolism; Kinetics; Methods. Procedures. Technologies; Molecular Structure; Monoamine Oxidase - metabolism; Monoamine Oxidase Inhibitors - pharmacology; Oxidation-Reduction; Pyridines - chemistry; Pyridines - metabolism; Pyridines - pharmacology; Stereoisomerism; Structure-Activity Relationship; Styrenes - chemistry; Styrenes - metabolism; Styrenes - pharmacology; Substrate Specificity; Organic cation; Enzyme; Nitrogen heterocycle; Iminium compounds; Enzyme inhibitor; Biological activity; Amine oxidase (flavin-containing); Stereoselectivity; Six membered ring; Vinylic compound; Oxidation; Oxidoreductases; Enzymatic reaction
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00027a019

1-Methyl-1,2,3,6-tetrahydrostilbazole (MTHS) and its analogs are oxidized by monoamine oxidase (MAO) A at slow rates comparable to that for the structurally similar neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, but the rates of oxidation by MAO B vary over a wide range depending on the structure of the analog. MAO A oxidation of all of the analogs yielded nonhyperbolic kinetic patterns, with little difference between the cis and trans isomers. In contrast MAO B showed hyperbolic kinetics and distinct stereoselectivity for the cis isomers. The corresponding pyridinium forms of trans-MTHS and its analogs were more potent inhibitors of MAO A (Ki values between 0.3 and 5 microM) than of MAO B, for which the Ki values varied greatly. The data suggest that the stringency of the MAO A active site for the geometry of the substrate molecule is less strict than that of MAO B. With MAO B, any substitution on the phenyl ring can lead to dramatic changes in the substrate properties which may be explained by the different orientation of substrate at the active site of the enzyme. Molecular geometry but not the effects of the substituents was shown to be an important factor in determining the effectiveness of substrate oxidation by MAO B.