Abstract
A series of indolylmethylamine derivatives were assayed toward MAO-A and MAO-B inhibition. The K(i) values of these compounds are in the range from 0.8 to >10(6) nM for MAO-A or from 0.75 to 476000 nM for MAO-B. The most selective MAO-A or MAO-B inhibitors elicit a ratio of K(i) in the order of 1500 or 1000, respectively. Comparison of MAO-A and MAO-B CoMFA models showed that both the steric and electrostatic properties at the 5 position of the indole ring are determinant for MAO selectivity. Computational simulations of the complex between this part of the ligand and Phe-208 of MAO-A or Ile-199 of MAO-B, experimentally identified as responsible for substrate selectivity, allowed us to further characterize the nature of these enzyme-inhibitor interactions.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amines / chemical synthesis*
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Animals
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Computer Simulation
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / pharmacology
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Isoenzymes / chemistry
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Isoenzymes / genetics
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Isoleucine / chemistry
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Kinetics
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Ligands
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Male
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Mitochondria, Liver / drug effects
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Mitochondria, Liver / enzymology
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Models, Molecular
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Monoamine Oxidase / chemistry*
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Monoamine Oxidase / genetics
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Monoamine Oxidase Inhibitors / chemical synthesis*
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Monoamine Oxidase Inhibitors / chemistry
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Monoamine Oxidase Inhibitors / pharmacology
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Phenylalanine / chemistry
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Rats
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Rats, Sprague-Dawley
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Structure-Activity Relationship
Substances
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Amines
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Indoles
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Isoenzymes
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Ligands
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Monoamine Oxidase Inhibitors
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Isoleucine
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Phenylalanine
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Monoamine Oxidase