Raines Douglas E, Gioia Fredrick, Claycomb Robert J, Stevens Renna J
Department of Anesthesia and Critical Care, Massachusetts General Hospital, 55 Fruit St., Boston, MA 02114, USA.
J Pharmacol Exp Ther. 2004 Oct;311(1):14-21. doi: 10.1124/jpet.104.069930. Epub 2004 May 27.
Benzene and several close structural analogs are inhaled drugs of abuse with general anesthetic activity. By virtue of their pi 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-pi 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-pi 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-pi interactions, weakly with hydrophobicity, and was independent of molecular volume. This is consistent with the hypothesis that cation-pi 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.
苯及几种结构相近的类似物是具有全身麻醉活性的吸入性滥用药物。凭借其π电子云，它们可能与蛋白质靶点上的阳离子原子电荷发生有吸引力的静电相互作用。在本研究中，我们检验了这样一个假设：吸入性滥用药物抑制人类N-甲基-D-天冬氨酸（NMDA）受体的效力与其参与阳离子-π相互作用的能力相关。采用电生理技术确定挥发性苯类似物对NR1/NR2B NMDA受体的抑制浓度，并利用计算机建模量化它们参与阳离子-π相互作用的能力及其分子体积。此外，还对每种化合物的辛醇/气分配系数（一种疏水性度量）进行了量化。所有18种化合物均以浓度依赖性方式可逆地抑制人类NR1/NR2B NMDA受体。NMDA受体抑制效力与参与阳离子-π相互作用的能力密切相关，与疏水性弱相关，且与分子体积无关。这与阳离子-π相互作用增强吸入性滥用药物与NMDA受体结合的假设一致，并表明这些药物的受体结合位点具有显著的阳离子特性。
