Abstract
Background: Many anesthetics modulate 3-transmembrane (such as NMDA) and 4-transmembrane (such as GABA<inf>A</inf>) 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<inf>A</inf> (α<inf>1</inf>β<inf>2</inf>γ<inf>2s</inf>) 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<inf>A</inf> 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<inf>A</inf> 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<inf>A</inf> 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.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 1-13 |
| Number of pages | 13 |
| Journal | BMC Pharmacology and Toxicology |
| DOIs | |
| State | Accepted/In press - Nov 19 2014 |
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ASJC Scopus subject areas
- Pharmacology (medical)
- Pharmacology
Cite this
Hydrocarbon molar water solubility predicts NMDA vs. GABA<inf>A</inf> receptor modulation. / Brosnan, Robert J; Pham, Trung L.
In: BMC Pharmacology and Toxicology, 19.11.2014, p. 1-13.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Hydrocarbon molar water solubility predicts NMDA vs. GABAA receptor modulation
AU - Brosnan, Robert J
AU - Pham, Trung L.
PY - 2014/11/19
Y1 - 2014/11/19
N2 - Background: 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. Methods: 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. Results: 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. 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.
AB - Background: 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. Methods: 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. Results: 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. 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.
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U2 - 10.1186/2050-6511-15-62
DO - 10.1186/2050-6511-15-62
M3 - Article
SP - 1
EP - 13
JO - BMC pharmacology & toxicology
JF - BMC pharmacology & toxicology
SN - 2050-6511
ER -