Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABA(A) receptors.
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Kumar M, Dillon GH
Assessment of direct gating and allosteric modulatory effects of meprobamate in recombinant GABA(A) receptors.
Eur J Pharmacol. 2016 Mar 15;775:149-58. doi: 10.1016/j.ejphar.2016.02.031. Epub 2016 Feb 9.
- PubMed ID
- 26872987 [ View in PubMed]
- Abstract
Meprobamate is a schedule IV anxiolytic and the primary metabolite of the muscle relaxant carisoprodol. Meprobamate modulates GABAA (gamma-aminobutyric acid Type A) receptors, and has barbiturate-like activity. To gain insight into its actions, we have conducted a series of studies using recombinant GABAA receptors. In alphaxbetazgamma2 GABAA receptors (where x=1-6 and z=1-3), the ability to enhance GABA-mediated current was evident for all alpha subunit isoforms, with the largest effect observed in alpha5-expressing receptors. Direct gating was present with all alpha subunits, although attenuated in alpha3-expressing receptors. Allosteric and direct effects were comparable in alpha1beta1gamma2 and alpha1beta2gamma2 receptors, whereas allosteric effects were enhanced in alpha1beta2 compared to alpha1beta2gamma2 receptors. In "extrasynaptic" (alpha1beta3delta and alpha4beta3delta) receptors, meprobamate enhanced EC20 and saturating GABA currents, and directly activated these receptors. The barbiturate antagonist bemegride attenuated direct effects of meprobamate. Whereas pentobarbital directly gated homomeric beta3 receptors, meprobamate did not, and instead blocked the spontaneously open current present in these receptors. In wild type homomeric rho1 receptors, pentobarbital and meprobamate were ineffective in direct gating; a mutation known to confer sensitivity to pentobarbital did not confer sensitivity to meprobamate. Our results provide insight into the actions of meprobamate and parent therapeutic agents such as carisoprodol. Whereas in general actions of meprobamate were comparable to those of carisoprodol, differential effects of meprobamate at some receptor subtypes suggest potential advantages of meprobamate may be exploited. A re-assessment of previously synthesized meprobamate-related carbamate molecules for myorelaxant and other therapeutic indications is warranted.
DrugBank Data that Cites this Article
- Drug Targets
Drug Target Kind Organism Pharmacological Action Actions Carisoprodol Gamma-aminobutyric acid receptor subunit alpha-1 Protein Humans UnknownActivatorModulatorDetails Carisoprodol Gamma-aminobutyric acid receptor subunit alpha-3 Protein Humans UnknownModulatorDetails Carisoprodol Gamma-aminobutyric acid receptor subunit alpha-5 Protein Humans UnknownModulatorDetails Carisoprodol Gamma-aminobutyric acid receptor subunit beta-2 Protein Humans UnknownModulatorDetails