Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABA_A receptor ligand MP-III-024

γ-Aminobutyric acid type A (GABA_A) receptors are located in spinal nociceptive circuits where they modulate the transmission of pain sensory signals from the periphery to higher centers. Benzodiazepine-type drugs bind to GABA_A receptors containing α1, α2, α3, and α5 subunits (α1GABA_A, α2GABA_A, α3GABA_A and α5GABA_A receptors, respectively) through which they inhibit the transmission of these signals. In the present study we describe the novel benzodiazepine site positive allosteric modulator modulator methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024). MP-III-024 displayed preference for α2GABA_A and α3GABA_A receptors relative to α1GABA_A and α5GABA_A receptors as well as an improved metabolic profile relative to subtype-selective positive modulators that are available currently. Administration of MP-III-024 resulted in a dose- and time-dependent reversal of mechanical hyperalgesia. On locomotor activity and schedule-controlled responding, MP-III-024 was ineffective across the doses tested. These data provide further evidence that α2GABA_A and α3GABA_A receptors play an important role in the antihyperalgesic effects and may not be involved in some of the undesired effects of benzodiazepine-like drugs. Further, these findings suggest that MP-III-024 is a suitable research tool for investigating the role of α2GABA_A and α3GABA_A receptors in the behavioral properties of benzodiazepine-like drugs in mice.