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

Electrostatic interactions are being increasingly recognized as important modulators of anesthetic action. By virtue of their π 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 π electron clouds inhibit human N-methyl-d-aspartate (NMDA) receptors with potencies that correlate with their abilities to engage in cation-π interactions. Electrophysiological techniques were used to define the NMDA receptor inhibitory potencies of anesthetics containing π electron clouds and computer modeling was used to quantify their abilities to engage in cation-π 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-π interactions and weakly with hydrophobicity. These results provide strong evidence that electrostatic cation-π interactions modulate the NMDA receptor inhibitory potencies of volatile anesthetics possessing π 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.