GABA_A Receptor Modulation by Phenyl Ring Compounds Is Associated with a Water Solubility Cut-Off Value

Abstract

Background: The modulation of N-methyl-D-aspartate receptors is associated with a molar water solubility cut-off effect of approximately 1.1 mmol/l and hence are unaffected by significantly less soluble compounds. However, compounds with this molar water solubility are still able to modulate γ-aminobutyric acid type A (GABA_A) receptors. We hypothesized that GABA_A receptor modulation by phenolic compounds would exhibit cut-off at a molar water solubility value less than 1.1 mmol/l. Methods: GABA_A receptors consisting of human α₁ and rat β₂ and γ_2s subunits were expressed in Xenopus laevis oocytes, and drug responses were measured using standard 2-electrode voltage clamp techniques. Twenty substituted phenols and benzenes of similar size and molecular volume were studied at saturated aqueous concentrations. Reversible and statistically significant change in GABA_A receptor current that was 10% or greater in magnitude from the baseline response defined a positive drug effect. Results: All phenyl ring compounds with a molar water solubility value equal to or greater than 0.46 mmol/l positively modulated GABA_A receptor currents. No compounds with a molar water solubility value equal to or less than 0.10 mmol/l had any effect on GABA_A receptor currents. Saturated solutions of phenols with 2,6-dimethyl and 2,6-diisopropyl substituents also caused channel opening in the absence of GABA. Conclusions: The molar water solubility cut-off for GABA_A receptor modulation by phenyl ring compounds lies between 0.10 and 0.46 mmol/l. Data suggest that hydrocarbons, perhaps including inhaled anesthetics, might modulate GABA_A receptors by displacing water from one or more low-affinity amphipathic binding sites to induce conformational changes that increase ion conductance.

In vitro and in vivo GABA_A Receptor Interaction of the Propanidid Metabolite 4-(2-[Diethylamino]-2-Oxoethoxy)-3-Methoxy-Benzeneacetic Acid

“…Direct GABA A receptor activation might result from DOMBA binding to the γ-subunit itself or to an interfacial location between the α-γ or β-γ subunits, since GABA A receptors required a γ-subunit for DOMBA to open the channel without an endogenous ligand. Negative modulation of the GABA-bound receptor may occur at a second site that is possibly located at or near volatile anesthetic binding sites where low-affinity interactions between sufficiently water soluble hydrocarbons and putative water-filled protein pockets have been postulated [9,10]. Alternatively, it might seem plausible that DOMBA could also produce both direct activation and negative modulatory effects by acting as partial agonist at a single GABA-binding site on the GABA A receptor while simultaneously competitively inhibiting binding of the full agonist GABA molecule.…”

“…DOMBA is very soluble in water at physiologic pH, and recent studies have shown that a wide variety of hydrocarbons with sufficient molar water solubility can engage in low-affinity GABA A receptor interactions [9,10]. Higher metabolite concentrations might manifest GABA A receptor effects, and such concentrations could become clinically relevant in patients with renal insufficiency where impaired clearance during prolonged drug infusions could produce a higher than expected metabolite plasma concentration (Cp).…”

Preparation and Measuring of Brain GABAAR‐coupled Cl‐/HCO3‐‐ Activity for Integral Assessment of Aquatic Toxicity

“…The GABA A Rs contain binding sites for various GABA A ergic ligands and can allosterically modulated by various therapeutic drugs, including barbiturates, benzodiazepines, anesthetics, neurosteroids, and ethanol (Sieghart, 2015). Moreover, the available literature also indicates that many phenolic compounds (including phenols) undergo high affinity interactions with receptor complexes and can modulate their functional activity (Brosnan & Pham, 2016). The GABA A receptor, which is an enzyme-linked receptor, is a transmembrane receptor in which the binding of an extracellular ligand causes enzymatic activity on the intracellular side.…”

“…The GABA A receptor, which is an enzyme-linked receptor, is a transmembrane receptor in which the binding of an extracellular ligand causes enzymatic activity on the intracellular side. This molecular organization of the receptor/enzyme complex determines its functional properties and its capacity for modulation by various phenolics (Aoshima, Hossain, Imamura, & Shingai, 2001;Brosnan & Pham, 2016).…”

“…Current Protocols in Toxicology Brosnan, R. J., & Pham, T. L. (2016). GABA A Receptor modulation by phenyl ring compounds is associated with a water solubility cut-off value.…”