title: Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABAAreceptor ligand MP-III-024.
abstract: γ-Aminobutyric acid type A (GABAA) 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 GABAAreceptors containing α1, α2, α3, and α5 subunits (α1GABAA, α2GABAA, α3GABAAand α5GABAAreceptors, 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 α2GABAAand α3GABAAreceptors relative to α1GABAAand α5GABAAreceptors 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 α2GABAAand α3GABAAreceptors 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 α2GABAAand α3GABAAreceptors in the behavioral properties of benzodiazepine-like drugs in mice.
authors.affiliation: Cooper Medical School of Rowan University, Department of Biomedical Sciences Camden, NJ 08103, USA. Electronic address: fischerb@rowan.edu.
authors.forename: Bradford D
authors.initials: BD
authors.lastname: Fischer
authors.affiliation: Cooper Medical School of Rowan University, Department of Biomedical Sciences Camden, NJ 08103, USA.
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Schlitt
authors.affiliation: Cooper Medical School of Rowan University, Department of Biomedical Sciences Camden, NJ 08103, USA.
authors.forename: Bryan Z
authors.initials: BZ
authors.lastname: Hamade
authors.affiliation: Medical University of Vienna, Department of Molecular Neurosciences, 1090 Vienna, Austria.
authors.forename: Sabah
authors.initials: S
authors.lastname: Rehman
authors.affiliation: Medical University of Vienna, Department of Molecular Neurosciences, 1090 Vienna, Austria.
authors.forename: Margot
authors.initials: M
authors.lastname: Ernst
authors.affiliation: University of Wisconsin-Milwaukee, Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, Milwaukee, WI 53201, USA.
authors.forename: Michael M
authors.initials: MM
authors.lastname: Poe
authors.affiliation: University of Wisconsin-Milwaukee, Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, Milwaukee, WI 53201, USA.
authors.forename: Guanguan
authors.initials: G
authors.lastname: Li
authors.affiliation: University of Wisconsin-Milwaukee, Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, Milwaukee, WI 53201, USA.
authors.forename: Revathi
authors.initials: R
authors.lastname: Kodali
authors.affiliation: University of Wisconsin-Milwaukee, Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, Milwaukee, WI 53201, USA.
authors.forename: Leggy A
authors.initials: LA
authors.lastname: Arnold
authors.affiliation: University of Wisconsin-Milwaukee, Department of Chemistry and Biochemistry and the Milwaukee Institute for Drug Discovery, Milwaukee, WI 53201, USA.
authors.forename: James M
authors.initials: JM
authors.lastname: Cook
mesh_terms: D000818:Animals; D001569:Benzodiazepines / Q000494:pharmacology*; D003975:Diazepam / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D058785:GABA-A Receptor Agonists / Q000494:pharmacology*; D006930:Hyperalgesia / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology; D008024:Ligands; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D011963:Receptors, GABA-A / Q000378:metabolism; D005680:gamma-Aminobutyric Acid
chemical_list: D058785:GABA-A Receptor Agonists; D007093:Imidazoles; D008024:Ligands; D011963:Receptors, GABA-A; D001569:Benzodiazepines; D005680:gamma-Aminobutyric Acid; D003975:Diazepam
keywords: Antihyperalgesia; Behavior; Benzodiazepine; GABA receptors; Pain