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Pharmacol Biochem Behav. 2019 Feb 27;180:22-31. doi: 10.1016/j.pbb.2019.02.013. [Epub ahead of print]

The α2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats.

Author information

1
The Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA; Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA; Laboratory of Antiepileptic Drug Discovery, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA. Electronic address: witkinconsult@gmail.com.
2
The Lilly Research Labs, Eli Lilly and Company, Indianapolis, IN, USA.
3
Millsaps College, Jackson, MS, USA.
4
Department of Psychiatry and Human Behavior, University of Mississippi Medical Center, Jackson, MS, USA.
5
Department of Physiology and Biophysics, University of Mississippi Medical Center, Jackson, MS, USA.
6
Department of Chemistry & Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, USA.
7
Department of Pharmacology, University of Arizona, Tucson, AZ, USA.
8
Laboratory of Antiepileptic Drug Discovery, Department of Neurological Surgery, Indiana University School of Medicine, Indianapolis, IN, USA.

Abstract

Clinical evidence indicates that positive allosteric modulators (PAMs) of GABAA receptors have analgesic benefit in addition to efficacy in anxiety disorders. However, the utility of GABAA receptor PAMs as analgesics is compromised by the central nervous system side effects of non-selective potentiators. A selective potentiator of GABAA receptors associated with α2/3 subunits, KRM-II-81(5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepin-3-yl)oxazole), has demonstrated anxiolytic, anticonvulsant, and antinociceptive effects in rodents with reduced motoric side effects. The present study evaluated the potential of KRM-II-81 as a novel analgesic. Oral administration of KRM-II-81 attenuated formalin-induced flinching; in contrast, diazepam was not active. KRM-II-81 attenuated nociceptive-associated behaviors engendered by chronic spinal nerve ligation (L5/L6). Diazepam decreased locomotion of rats at the dose tested in the formalin assay (10 mg/kg) whereas KRM-II-81 produced small decreases that were not dose-dependent (10-100 mg/kg). Plasma and brain levels of KRM-II-81 were used to demonstrate selectivity for α2/3- over α1-associated GABAA receptors and to define the degree of engagement of these receptors. Plasma and brain concentrations of KRM-II-81 were positively-associated with analgesic efficacy. GABA currents from isolated rat dorsal-root ganglion cultures were potentiated by KRM-II-81 with an ED50 of 32 nM. Measures of respiratory depression were reduced by alprazolam whereas KRM-II-81 was either inactive or produced effects with lower potency and efficacy. These findings add to the growing body of data supporting the idea that α2/3-selective GABAA receptor PAMs will have efficacy and tolerability as pain medications including those for neuropathic pain. Given their predicted anxiolytic effects, α2/3-selective GABAA receptor PAMs offer an additional inroad into the management of pain.

PMID:
30825491
DOI:
10.1016/j.pbb.2019.02.013

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