Hydrocarbon molar water solubility predicts NMDA vs. GABA(A) receptor modulation

BACKGROUND: Many anesthetics modulate 3-transmembrane (such as NMDA) and 4-transmembrane (such as GABA(A)) receptors. Clinical and experimental anesthetics exhibiting receptor family specificity often have low water solubility. We hypothesized that the molar water solubility of a hydrocarbon could be used to predict receptor modulation in vitro. METHODS: GABA(A) (α(1)β(2)γ(2s)) or NMDA (NR1/NR2A) receptors were expressed in oocytes and studied using standard two-electrode voltage clamp techniques. Hydrocarbons from 14 different organic functional groups were studied at saturated concentrations, and compounds within each group differed only by the carbon number at the ω-position or within a saturated ring. An effect on GABA(A) or NMDA receptors was defined as a 10% or greater reversible current change from baseline that was statistically different from zero. RESULTS: Hydrocarbon moieties potentiated GABA(A) and inhibited NMDA receptor currents with at least some members from each functional group modulating both receptor types. A water solubility cut-off for NMDA receptors occurred at 1.1 mM with a 95% CI = 0.45 to 2.8 mM. NMDA receptor cut-off effects were not well correlated with hydrocarbon chain length or molecular volume. No cut-off was observed for GABA(A) receptors within the solubility range of hydrocarbons studied. CONCLUSIONS: Hydrocarbon modulation of NMDA receptor function exhibits a molar water solubility cut-off. Differences between unrelated receptor cut-off values suggest that the number, affinity, or efficacy of protein-hydrocarbon interactions at these sites likely differ.