Brosnan RJ and Pham TL (2014), Hydrocarbon molar water solubility predicts NMD...

XB-ART-51091

BMC Pharmacol Toxicol 2014 Nov 19;15:62. doi: 10.1186/2050-6511-15-62.

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Hydrocarbon molar water solubility predicts NMDA vs. GABAA receptor modulation.

Brosnan RJ , Pham TL .

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Many anesthetics modulate 3-transmembrane (such as NMDA) and 4-transmembrane (such as GABAA) 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. GABAA (α1β2γ2s) 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 GABAA or NMDA receptors was defined as a 10% or greater reversible current change from baseline that was statistically different from zero. Hydrocarbon moieties potentiated GABAA 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 GABAA receptors within the solubility range of hydrocarbons studied. 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.

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Species referenced: Xenopus laevis
Genes referenced: gabarap tpm3

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	Figure 1. Summary of ion channel modulation as a function of calculated anesthetic molar solubility in unbuffered water at 25°C (values from SciFinder Scholar). Drugs that modulate 4-transmembrane receptors (TM4) or neither receptor type are shown as open circles (○, A-F) below the dotted horizontal solubility line. Drugs that modulate both 3-transmembrane (TM3) and TM4 receptors are shown as small black circles (●, G-U) above the dotted horizontal solubility line. A = nonane (unpublished data), B = midazolam [9], C = diazepam [10], D = undecanol [11], E = etomidate [12], F = 1,2-dichlorohexafluorocyclobutane [13], G = sevoflurane [14–17], H = propofol [18, 19], I = ketamine [12, 16, 20], J = isoflurane [14–16, 21, 22], K = enflurane [15, 23], L = dizocilpine [20, 24], M = desflurane [16, 17], N = halothane [14, 22, 23], O = cyclopropane [22, 25], P = chloroform [22], Q = 2,6-dimethylphenol [26], R = methoxyflurane [14, 15, 23], S = diethyl ether [15, 23], T = nitrous oxide [21, 22], U = ethanol [21].
	Figure 2. Sample two-electrode voltage clamp recordings from oocytes expressing either GABA A receptors (left) or NMDA receptors (right). Black bars (▬) represent periods of agonist exposure, and arrows (↔) represent periods of saturated alkane exposure. Both butane and pentane positively modulate GABAA receptors. Butane negatively modulates NMDA receptors, but pentane produces no effect. Hence, NMDA receptors exhibit an alkane cut-off between butane and pentane.
	Figure 3. Summary of receptor cut-off effects as a function of molar water solubility for compounds tested in Tables 1 and 2 . For each hydrocarbon functional group, white bars represent compounds that modulate both GABAA and NMDA receptors, and black bars represent compounds that modulate GABAA receptors but have no effect on NMDA receptors at a saturating concentration. Intervening grey bars represent solubility values for which no data exist.
	Figure 4. Summary of receptor cut-off effects as a function of the number of drug carbon atoms for compounds tested in Tables 1 and 2 . For each hydrocarbon functional group, white bars represent compounds that modulate both GABAA and NMDA receptors, and black bars represent compounds that modulate GABAA receptors but have no effect on NMDA receptors at a saturating concentration. Intervening grey bars represent solubility values for which no data exist. No receptor cut-off pattern is evident as a function of the number of drug carbon atoms.
	Figure 5. Summary of receptor cut-off effects as a function of the calculated molecular volume of each drug for compounds tested in Tables 1 and 2 . For each hydrocarbon functional group, white bars represent compounds that modulate both GABAA and NMDA receptors, and black bars represent compounds that modulate GABAA receptors but have no effect on NMDA receptors at a saturating concentration. Intervening grey bars represent solubility values for which no data exist. No receptor cut-off pattern is evident as a function of molecular volume.

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