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

Abstract

Benzene and several close structural analogs are inhaled drugs of abuse with general anesthetic activity. By virtue of their 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 cationinteractions. 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-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-interactions, weakly with hydrophobicity, and was independent of molecular volume. This is consistent with the hypothesis that cation-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.

Inhalants

“…Interestingly, toluene had no significant effects on the closely related AMPA and kainate receptors at concentrations that were effective to block NMDA receptors. Similar results were found for benzene, m-xylene, and ethylbenzene, propylbenzene, 1,1,1-trichloroethane (TCE) (Cruz et al, 2000), and a number of other volatile benzene analogs (Raines et al, 2004).…”

Effects of Anesthetics on Mutant N-Methyl-d-Aspartate Receptors Expressed in Xenopus Oocytes

“…Equally striking was the complete lack of effect of the mutations on the actions of nitrous oxide and benzene. Recently, Raines et al (2004) reported that aromatic anesthetic compounds, such as benzene, inhibited NR1/NR2B receptors and demonstrated that the inhibitory potency was independent of molecular volume, but it correlated strongly with the ability to engage in cation-interactions. This interaction between electrons in aromatic compounds and cationic charges in protein residues is recognized as an important molecular force for binding of ligands to receptor targets.…”

“…Benzene has been shown to inhibit function of the wildtype NMDA receptors (Raines et al, 2004), and we tested this compound on the mutant receptors. The inhibitory action of benzene was not affected by mutation of NR1, NR2A, or the combined mutations (Fig.…”

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

“…The present work describes the use of ab initio computational modeling and electrophysiological techniques to test the hypothesis that cation-k interactions modulate the NMDA receptor inhibitory potencies of aromatic anesthetics [7].…”