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

  title={The $\alpha$2,3-selective potentiator of GABAA receptors, KRM-II-81, reduces nociceptive-associated behaviors induced by formalin and spinal nerve ligation in rats},
  author={J. Witkin and R. Černe and P. Davis and K. Freeman and J. Carmo and J. K. Rowlett and K. R. Methuku and A. Okun and S. Gleason and X. Li and M. Krambis and M. Poe and G. Li and J. Schkeryantz and R. Jahan and L. Yang and W. Guo and L. K. Golani and W. H. Anderson and J. Catlow and T. M. Jones and F. Porreca and J. L. Smith and K. Knopp and J. Cook},
  journal={Pharmacology Biochemistry and Behavior},
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… Expand
The α2,3-selective potentiators of GABAA receptors, KRM-II-81 and MP-III-80, produce anxiolytic-like effects and block chemotherapy-induced hyperalgesia in mice without tolerance development
Subchronic dosing for 22 days with KRM-II-81 and MP-III-80 demonstrated enduring analgesic efficacy without tolerance development; the antihyperalgesic effects of gabapentin showed evidence of tolerance development. Expand
The Positive Allosteric Modulator of α2/3-Containing GABAA Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury
  • J. Witkin, G. Li, +8 authors X. Jin
  • Medicine
  • The Journal of Pharmacology and Experimental Therapeutics
  • 2019
The imidizodiazepine KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy. Expand
Synergistic antihyperalgesic and antinociceptive effects of morphine and methyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo[1,5-a][1,4]diazepine-3-carboxylate (MP-III-024): a positive allosteric modulator at α2GABAA and α3GABAA receptors.
These results demonstrate an interaction between α2GABAA and α3GabAA receptor- and μ-opioid receptor-mediated signals and suggest that combination therapy may be useful for the treatment of pain-related disorders. Expand
The Imidazodiazepine Anticonvulsant, KRM-II-81, Produces Novel, Non-diazepam-like Antiseizure Effects.
In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than that of DZP, and blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. Expand
Improvements in the Pharmacological Profile of Diazepam by KRM-II-81, an Imidazodiazepine Positive Allosteric Modulator of 2/3-Containing GABAA Receptors: Preclinical Data Predict Enhanced Efficacy for Epilepsy, Chronic Pain, Anxiety, and Depression
Improvements in the Pharmacological Profile of Diazepam by KRM-II-81, an Imidazodiazepine Positive Allosteric Modulator of 2/3-Containing GABAA Receptors: Preclinical Data Predict Enhanced EfficacyExpand
Subtype selective γ-Aminobutyric Acid Type A Receptor (GABAAR) Modulators Acting at the Benzodiazepine Binding Site: An Update.
The current state of the field of subtype-selective GABAAR modulators acting via the BZD binding site and their potential clinical indications are summarized. Expand
A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor
It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors. Expand
Pentameric Ligand-Gated Ion Channels as Pharmacological Targets Against Chronic Pain
Experimental data have shown that novel allosteric modulators targeting the excitatory nicotinic acetylcholine receptor, as well as the inhibitory GABAA and glycine receptors, reverse chronic pain-related behaviors in preclinical assays, which strongly suggest the pharmacological modulation of pentameric ligand-gated ion channels is a promising strategy towards the development of novel therapeutics to treat chronic pain states in humans. Expand
Pharmacological Analysis of the Anti-inflammatory and Antiallodynic Effects of Zinagrandinolide E from Zinnia grandiflora in Mice.
The anti-inflammatory and antiallodynic activities of ZGE are multitarget; these involve the opioidergic, serotoninergic, and GABAergic systems, as well as the NO-cGMP-ATP-sensitive K+ channel signaling pathway. Expand
The value of human epileptic tissue in the characterization and development of novel antiepileptic drugs: The example of CERC-611 and KRM-II-81
Preclinical data on these compounds argue that patient-based biological data increase the probability that a newly discovered molecule will translate its antiepileptic potential to patients. Expand


Effects of the α2/α3-subtype-selective GABAA receptor positive allosteric modulator KRM-II-81 on pain-depressed behavior in rats: comparison with ketorolac and diazepam
The effectiveness of ketorolac to block acid-induced ICSS depression agrees with clinical analgesic efficacy of ketOrolac, and KRM-II-81 produced significant but less consistent and shorter-acting antinociception than ket orolac. Expand
Pharmacological and antihyperalgesic properties of the novel α2/3 preferring GABAA receptor ligand MP-III-024
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.Expand
Improved Synthesis of Anxiolytic, Anticonvulsant and Antinociceptive α2/α3-GABA(A)ergic Receptor Subtype Selective Ligands as Promising Agents to Treat Anxiety, Epilepsy, as well as Neuropathic Pain.
An improved synthesis of the anxiolytic, anticonvulsant and antinociceptive compounds: Hz-166, and its bioisosteres 1,2,4-oxadiazole (MP-III-080) and 1,3-oxazole (KRM-II-81) were executed in higherExpand
Further evaluation of the potential anxiolytic activity of imidazo[1,5-a][1,4]diazepin agents selective for α2/3-containing GABAA receptors
The data support the following conclusions: ancillary pharmacological actions of compound 8 might be responsible for its lack of anxiolytic‐like efficacy despite its efficacy as an anticonvulsant, and replacement of the ester function with suitable heterocycles markedly improves bioavailability and engenders molecules with the opportunity to have potent and efficacious effects in vivo that correspond to human anxIOlytic actions. Expand
Positive allosteric modulators of nonbenzodiazepine &ggr;-aminobutyric acidA receptor subtypes for the treatment of chronic pain
2-261 may produce pain relief with diminished side effects through selective modulation of &bgr;2/3-subunit–containing extrasynaptic GABAARs. Expand
Genuine antihyperalgesia by systemic diazepam revealed by experiments in GABAA receptor point-mutated mice
It is concluded that systemic diazepam exerts a genuine antihyperalgesic effect, which depends on spinal GABAA receptors containing α2 and/or α3 subunits, which reduced formalin‐induced flinching in wild‐type mice. Expand
Pharmacological discrimination of GluR5 and GluR6 kainate receptor subtypes by (3S,4aR,6R,8aR)-6-[2-(1(2)H-tetrazole-5-yl)ethyl]decahyd roisdoquinoline-3 carboxylic-acid.
The selective antagonism by LY293558 of GLUR5 receptors should allow the determination of the functional role of GluR5 and GluGluR6 in more complex systems. Expand
Antinociceptive Effects of a Novel α2/α3-Subtype Selective GABAA Receptor Positive Allosteric Modulator.
KRM-II-81 is a selective α2/α3 subtype GABAA PAM with significant antinociceptive effects in chemical stimulation-induced pain in mice, and similar efficacy at α1/α2/ α3 subtypes with similar potency is demonstrated. Expand
Antihyperalgesia by α2-GABAA Receptors Occurs Via a Genuine Spinal Action and Does Not Involve Supraspinal Sites
The results indicate that drugs that specifically target α2-GABAARs exert their antihyperalgesic effect through enhanced spinal nociceptive control, and such drugs may be well-suited for the systemic treatment of different chronic pain conditions. Expand
GABAA receptor subtype-selective modulators. I. α2/α3-selective agonists as non-sedating anxiolytics.
  • J. Atack
  • Chemistry, Medicine
  • Current topics in medicinal chemistry
  • 2011
T attempts were made to identify subtype-selective compounds that modulate α2/α3 but not α1 receptor function with the prediction that such compounds would be non-sedating anxiolytics, and a structurally-related class of imidazopyridines was explored. Expand