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

Abstract

γ-aminobutyric acid type A (GABAA) receptors are located in spinal nociceptive circuits where they mediate the transmission of pain sensory signals from the periphery to higher centers. Benzodiazepine-type drugs bind GABAA, receptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAA, and α5GABAA receptors, respectively) through which they inhibit the transmission of these signals. However, the role of these different GABAA receptor subtypes in the antihyperalgisic properties of benzodiazepine-type drugs has not been characterized fully and is limited by currently available compounds. 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 α2GABAA and α3GABAA receptors relative to α1GABAA and α5GABAA receptors as well as an improved metabolic profile relative to subtype-selective positive modulators that are available currently. MP-III-024 produced a dose- and time-dependent reversal of mechanical sensitivity. On locomotor activity and schedule-controlled responding, MP-III-024 was ineffective across the doses tested. These data provide further evidence that α2GABAA and α3GABAA receptors play an important role in the antihyperalgiesic effects and may not be involved in some of the off target effects of benzodiazepine-like drugs. Further, these findings suggest that MP-III-024 is an ideal research tool for investigating the role of α2GABAA and α3GABAA receptors in the behavioral properties of benzodiazepine-like drugs in mice.

International Union of Basic and Clinical Pharmacology. CVI: GABAAReceptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans

“…13). MP-III-024 and KRM-II-81 exhibited significant antinociceptive effects (Fischer et al, 2017;Lewter et al, 2017). HZ166 produced some anticonvulsive (Rivas et al, 2009), anxiolytic-like (Savi c et al, 2010), and antihyperalgesic effects (Di Lio et al, 2011), while it was devoid of sedation and motor impairment in rodents in some (Rivas et al, 2009;Di Lio et al, 2011), but not all, studies (Savi c et al, 2010).…”

“…KRM-II-81, a derivative of HZ166 carrying an oxazole ring instead of the ethyl ester of HZ166, exhibited a higher potency and efficacy for a2b3g2 and a3b3g2 receptors (Lewter et al, 2017). However, the respective concentration-response curves indicate that all three of these compounds already at 100 nM concentrations significantly modulate a1 and a5 receptors in addition to a2/a3 receptors (Rivas et al, 2009;Fischer et al, 2010Fischer et al, , 2017Lewter et al, 2017) (Fig. 13).…”

“…13) exhibits a moderate affinity for the benzodiazepine site of GABA A receptor subtypes (K i of 300, 160, 527, or 82 nM for a1b3g2, a2b3g2, a3b3g2, or a5b3g2 receptors, respectively) (Fischer et al, 2010) and was claimed to be an a2/a3 GABA A receptor-selective benzodiazepine. MP-III-024, the methyl ester analog of the ethyl ester HZ166, exhibited a slightly lower efficacy than HZ166, but a similar preferential activity at a2b3g2 and a3b3g2 receptors (Fischer et al, 2017). KRM-II-81, a derivative of HZ166 carrying an oxazole ring instead of the ethyl ester of HZ166, exhibited a higher potency and efficacy for a2b3g2 and a3b3g2 receptors (Lewter et al, 2017).…”

Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABAA receptors: Improved bioavailability enhances anticonvulsant efficacy

“…In vivo proof of concept demonstrated that, in contrast to HZ-166, KRM-II-81 prevented the suppression of responding of rats in a Vogel conflict test (Poe et al, 2016), a result extended to other molecules in this series (Witkin et al, 2017) and thus demonstrating anxiolytic-like activity in this rodent model. This in vivo translation has been also extended with these molecules into the pain domain (Lewter et al, 2017;Fischer et al, 2017).…”

Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain

“…HZ166 did not generate neither locomotor impairment, sedation, nor tolerance (Di Lio et al, 2011). A newer BDZ-type drug, MP-III-024, is a a2/a3GABA A R PAM that displayed analgesic effects in inflamed mice without significant effects on the open field performance (Fischer et al, 2017). In the same line, KRM-II-81 is another a2/a3-selective GABA A R BDZsite ligand that displayed anti-nociceptive effects in rodents with reduced motor side effects (Lewter et al, 2017;Witkin et al, 2019).…”