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The N-Methyl-d-aspartate Receptor Inhibitory Potencies of Aromatic Inhaled Drugs of Abuse: Evidence for Modulation by Cation-π Interactions

Benzene and several close structural analogs are inhaled drugs of abuse with general anesthetic activity. By virtue of their π electron clouds, they may engage in attractive electrostatic interactions with cationic atomic charges on protein targets. In this study, we tested the hypothesis that inhaled drugs of abuse 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 NR1/NR2B NMDA receptor inhibitory concentrations of volatile benzene analogs, and computer modeling was used to quantify their abilities to engage in cation-π interactions and their molecular volumes. In addition, each compound's octanol/gas partition coefficient (a measure of hydrophobicity) was quantified. All 18 compounds 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, weakly with hydrophobicity, and was independent of molecular volume. This is consistent with the hypothesis that cation-π interactions enhance the binding of inhaled drugs of abuse to the NMDA receptor and suggests that the receptor binding site(s) for these drugs possesses significant cationic character.