Molecular determinants of MAO selectivity in a series of indolylmethylamine derivatives: biological activities, 3D-QSAR/CoMFA analysis, and computational simulation of ligand recognition

J Med Chem. 2000 May 4;43(9):1684-91. doi: 10.1021/jm991164x.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amines / chemical synthesis*
  • Animals
  • Computer Simulation
  • In Vitro Techniques
  • Indoles / chemical synthesis*
  • Indoles / pharmacology
  • Isoenzymes / chemistry
  • Isoenzymes / genetics
  • Isoleucine / chemistry
  • Kinetics
  • Ligands
  • Male
  • Mitochondria, Liver / drug effects
  • Mitochondria, Liver / enzymology
  • Models, Molecular
  • Monoamine Oxidase / chemistry*
  • Monoamine Oxidase / genetics
  • Monoamine Oxidase Inhibitors / chemical synthesis*
  • Monoamine Oxidase Inhibitors / chemistry
  • Monoamine Oxidase Inhibitors / pharmacology
  • Phenylalanine / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Structure-Activity Relationship

Substances

  • Amines
  • Indoles
  • Isoenzymes
  • Ligands
  • Monoamine Oxidase Inhibitors
  • Isoleucine
  • Phenylalanine
  • Monoamine Oxidase