Cation-ir interactions modulate the NMDA receptor inhibitory potencies of inhaled aromatic anesthetics

摘要

Electrostatic interactions are being increasingly recognized as important modulators of anesthetic action. By virtue of their pi electron clouds, aromatic anesthetics may engage in attractive electrostatic interactions with cationic atomic charges on protein targets. In this study, we tested the hypothesis that anesthetics containing pi electron clouds inhibit human N-methyl-D-aspartate (NMDA) receptors with potencies that correlate with their abilities to engage in cation-ir interactions. Electrophysiological techniques were used to define the NMDA receptor inhibitory potencies of anesthetics containing pi electron clouds and computer modeling was used to quantify their abilities to engage in cation-pi interactions. All 18 anesthetics inhibited human NR1/NR2B NMDA receptors reversibly and in a concentration-dependent manner. NMDA receptor inhibitory potency correlated strongly with the ability to engage in cation-ir interactions and weakly with hydrophobicity. These results provide strong evidence that electrostatic cation-ir interactions modulate the NMDA receptor inhibitory potencies of volatile anesthetics possessing it electron clouds. It suggests that the NMDA receptor inhibitory site for such anesthetics contains a positive charge and that computational modeling may be used to predict the NMDA receptor inhibitory potencies of volatile compounds.