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

gamma-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 alpha 1, alpha 2, alpha 3, and alpha 5 subunits (alpha 1 GABA(A), alpha 2GABA(A), alpha 3GABA(A) and alpha 5GABA(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-ethyny1-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]cliazepine-3-carboxylate (MP-III-024). MP-III-024 displayed preference for alpha 2GABA(A) and alpha 3GABA(A) receptors relative to alpha 1GABA(A) and alpha 5GABA(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 alpha 2GABA(A) and alpha 3GABA(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 alpha 2GABA(A) and alpha 3GABA(A) receptors in the behavioral properties of benzodiazepine-like drugs in mice. (C) 2017 Elsevier Inc. All rights reserved.