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

A series of indolylmethylamine derivatives were assayed toward MAO-A and MA O-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 selec tive MAO-A or MAO-B inhibitors elicit a ratio of K-i in the order of 1500 o r 1000, respectively. Comparison of MAO-A and MAO-B CoMFA models showed tha t both the steric and electrostatic properties at the 5 position of the ind ole 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-19 9 of MAO-B, experimentally identified as responsible for substrate selectiv ity, allowed us to further characterize the nature of these enzyme-inhibito r interactions.