A comparison of the molecular bases for N-methyl-D-aspartate-receptor inhibition versus immobilizing activities of volatile aromatic anesthetics.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: The similarities in the pharmacophoric maps are consistent with NMDA receptors contributing part of the immobilizing activity of volatile aromatic anesthetics.

Determinants of volatile general anesthetic potency: a preliminary three-dimensional pharmacophore for halogenated anesthetics.

We investigated the molecular basis for the immobilizing activity of halogenated volatile anesthetics using comparative molecular field analysis. In vivo potency data (expressed as minimum alveolar concentrations) for 69 structurally diverse anesthetics were obtained from the literature. The drugs were randomly divided into a training set (n = 52) used to derive the activity model and a test set (n = 17) used to independently assess the model's predictive power. The anesthetic structures were aligned so as to maximize their similarity in molecular shape and electrostatic potential to the most potent drug in the group, CF2H-(CF2)3-CH2OH. The conformers and alignments of the anesthetics with maximum similarity (calculated as Carbo indices) were retained and used to derive the comparative molecular field analysis models. The final model explained 94.2% of the variance in the observed activities of the training set compounds. The model showed good predictive capability for both the training set (cross-validated r2 = 0.705) and randomly excluded test set anesthetics (r2 = 0.837). Three-dimensional pharmacophoric maps were derived to identify the spatial distribution of key areas where steric and electrostatic interactions are important in determining immobilizing activity of the halogenated drugs and were compared with our previously published maps obtained for nonhalogenated volatile anesthetics.

Derivation of preliminary three-dimensional pharmacophores for nonhalogenated volatile anesthetics.

We investigated the molecular basis for the immobilizing activity of nonhalogenated volatile anesthetics by using comparative molecular field analysis (CoMFA). In vivo potency data (expressed as minimum alveolar anesthetic concentrations) for 38 structurally diverse drugs were obtained from the literature. The anesthetics were randomly divided into a training-set (n = 28) used to formulate the activity models and a test-set (n = 10) used to independently assess the models' predictive power. The anesthetic structures were aligned to maximize their similarity in molecular shape and electrostatic potential to conformers of the most active drug in the group: hexanol. The individual conformers and alignments with maximum similarity (calculated with combined Carbo indices) were retained and used to derive the CoMFA activity models. The final CoMFA model explained 95.5% of the variance in the observed activities of the training-set anesthetics. The model had good predictive capability for both the training-set drugs (cross-validated r(2) = 0.824) and the randomly excluded test-set anesthetics (r(2) = 0.921). Pharmacophoric maps were derived by identifying the spatial distribution of key areas in which steric and electrostatic interactions are important in determining the immobilizing activity of the anesthetics considered.