A Comparison of the Molecular Bases for N-Methyl-d-Aspartate-Receptor Inhibition Versus Immobilizing Activities of Volatile Aromatic Anesthetics

Abstract

Aromatic anesthetics exhibit a wide range of N-methyl-d-aspartate (NMDA) receptor inhibitory potencies and immobilizing activities. We sought to characterize the molecular basis of NMDA receptor inhibition using comparative molecular field analysis (CoMFA), and compare the results to those from an equivalent model for immobilizing activity. Published potency data for 14 compounds were supplemented with new values for 2 additional agents. The anesthetics were divided into a training set (n = 12) used to formulate the activity models and a test set (n = 4) used to independently assess the models' predictive capability. The anesthetic structures were geometry optimized using ab initio quantum mechanics and aligned by field-fit minimization to provide the best correlation between the steric and electrostatic fields of the molecules and one or more lead structures. Orientations that yielded CoMFA models with the greatest predictive capability (assessed by leave-one-out cross-validation) were retained. The final CoMFA model for the inhibition of NR1/NR2B NMDA receptors explained 99.3% of the variance in the observed activities of the 12 training set agents (F(2,)(9) = 661.5, P < 0.0001). The model effectively predicted inhibitory potency for the training set (cross-validated r(2)(CV) = 0.944) and 4 excluded test set compounds (predictive r(2)(Pred) = 0.966). The equivalent model for immobility in response to noxious stimuli explained 98.0% of the variance in the observed activities for the training set (F(2,)(9) = 219.2, P < 0.0001) and exhibited adequate predictive capability for both the training set (r(2)(CV) = 0.872) and test set (r(2)(Pred) = 0.926) agents. Comparison of pharmacophoric maps showed that several key steric and electrostatic regions were common to both activity models, but differences were observed in the relative importance of these key regions with respect to the two aspects of anesthetic activity. The similarities in the pharmacophoric maps are consistent with NMDA receptors contributing part of the immobilizing activity of volatile aromatic anesthetics.