Inhibition ofN-Methyl-d-aspartate Receptors by Straight-Chain Diols: Implications for the Mechanism of the Alcohol Cutoff Effect

Abstract

n-Alkanol inhibition of N-methyl-D-aspartate (NMDA) receptors exhibits a "cutoff" effect: alcohols with up to eight to nine carbon atoms inhibit the receptor, whereas larger alcohols do not. This phenomenon was originally proposed to result from size exclusion; i.e., alcohols above the cutoff are too large to bind to an amphiphilic site on the receptor. In the present study, 1,⍀-diols with 3 to 14 carbon atoms inhibited NMDA-activated current in Chinese hamster ovary and human embryonic kidney 293 cells transiently expressing NR1 and NR2B NMDA receptor subunits. Results of fluctuation analysis experiments were consistent with a similar mechanism of inhibition of NMDA-activated current by alcohols and diols. The average change in apparent energy of binding of the diols caused by addition of a methylene group was 2.1 kJ/mol, which is consistent with an important role of hydrophobic interactions. Because 1,⍀-diols with 9 to 14 carbons inhibited NMDA-activated current, despite having molecular volumes exceeding that at the cutoff point for 1-alkanols, a size exclusion mechanism seems inadequate to explain the cutoff effect. A disparity in hydrophobicity values at the cutoff for alcohols and diols, however, revealed that hydrophobicity could also not entirely explain the cutoff phenomenon. From these results, it seems that the cutoff effect on NMDA receptors results primarily from the inability of longchain alcohols to achieve adequate concentrations at their site of action due to low aqueous solubility, although other factors may also contribute to the effect.N-Methyl-D-aspartate (NMDA) receptor-ion channels are believed to be important targets of alcohol action in the central nervous system. Previous studies from this and other laboratories have demonstrated that n-alcohol inhibition of NMDA receptor-ion channels exhibits a "cutoff" effect: as a series of straight-chain alcohols is ascended, inhibitory potency of the alcohols increases up to a chain length of eight to nine carbon atoms then declines beyond the cutoff point and eventually disappears (Peoples and

A discrete alcohol pocket involved in GIRK channel activation

“…It is notable that MPD predominantly activates GIRK channels in contrast to large primary alcohol of similar size. A functional difference between diols and primary alcohols has been reported previously for NMDA channels32. The addition of a hydroxyl group may lead to decreased sensitivity to inhibition for GIRK channels.…”

γ-Aminobutyric Acid Type A Receptor Modulation by Etomidate Analogs

“…26–28 A linear fit of the logarithm-transformed values of this relationship yielded a slope that is not significantly different from zero (0.13 ± 0.20, p = 0.5271) and an r 2 of only 0.019. An analogous linear fit of the logarithm-transformed relationship between of hypnotic potency in rats and octanol:buffer partition coefficient similarly yielded a slope that was not significantly different from zero (0.09 ± 0.30, p = 0.7562) and an r 2 of only 0.005 (data not shown).…”

Evidence that ethanol acts on a target in Loop 2 of the extracellular domain of α1 glycine receptors

“…We also tested alkanediols (diols) in order to investigate the possibility that the reduced decanol potency following PMTS exposure reflected its lower solubility compared to octanol (Peoples and Ren 2002). The responses by the diols paralleled those observed with n ‐alcohols of the same length (Fig.…”

“…To investigate whether position 52 is part of an alcohol pocket, we tested the effects of octanol and decanol on A52C GlyRs, before and after PMTS exposure, using the general procedures described for sequential applications. We also tested the respective diols (1,8‐octanediol; 1,10‐decanediol) to minimize confounds from reduced solubility that occurs as the alcohol chain length increases (Peoples and Ren 2002). We limited the concentration and range of n ‐alcohols used in this study based on previous work that established alcohol cutoff in WT and S267C GlyRs (Wick et al.…”