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

Witkin, Jeffrey M.; Cerne, Rok; Davis, Paula G.; Freeman, Kevin B.; Carmo, Jussara M. do; Rowlett, James K.; Methuku, Kashi Reddy; Okun, Alec; Gleason, Scott D.; Li, X.; Krambis, Michael J.; Poe, M.; Li, G.; Schkeryantz, Jeffrey M.; Jahan, Rajwana; Yang, Lijuan; Guo, Wen; Golani, Lalit K.; Anderson, Wesley; Catlow, John T.; Jones, Thomas M.; Porreca, Frank; Smith, Jodi L.; Knopp, Kelly L.; Cook, James M.

doi:10.1016/j.pbb.2019.02.013

Cited by 30 publications

(28 citation statements)

References 53 publications

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“…The selectivity of these compounds for 5-containing GABA A receptors dictates that they have less or no influence on GABA A receptors associated with other alpha subunits. Compounds modulating GABA A receptors associated with other alpha subunits can engender somnolence and sedation (1) [45], anxiolytic, antiepileptic, and antinociceptive effects (2/3) [46][47][48]. The structures of the 5-selective GABA A receptor modulators discussed in the present paper are shown in Figure 1.…”

Section: Alpha-5-containing Gaba a Receptorsmentioning

confidence: 89%

Facilitation of Social Support through Negative Allosteric Modulation of α5-Associated GABAA Receptors: A Novel Mechanism for the Treatment of Depression, Agitation, and Aggression in the Elderly

Witkin¹,

Golani²,

Cerne³

et al. 2019

obm geriatr

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Major depressive disorder is a highly-prevalent and debilitating disorder in the aged population. Accumulating clinical evidence suggests a key role for social support in helping to mitigate depression. Preclinical data are reviewed that indicate that selective negative allosteric modulation of 5-containing GABA A receptors, as with RY-080, might rapidly impact depression in patients. Further, preclinical data in transgenic mice modeling neurodegenerative diseases has suggested that this mechanism might also function to reduce agitation and aggression. These data are discussed in terms of the concept of

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Section: Alpha-5-containing Gaba a Receptorsmentioning

confidence: 89%

Facilitation of Social Support through Negative Allosteric Modulation of α5-Associated GABAA Receptors: A Novel Mechanism for the Treatment of Depression, Agitation, and Aggression in the Elderly

Witkin¹,

Golani²,

Cerne³

et al. 2019

obm geriatr

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“…The GABA A receptor function, and finally its physiologic effect, can be modified both by agents that, such as bicuculline, interact directly with the receptor recognition site (orthosteric sites), and by agents that interact with sites other than the GABA ligand-binding domain (allosteric sites), such as benzodiazepines, barbiturates and neurosteroids [42,49]. Effectively, several GABA A selective allosteric modulators exert antinociceptive activity on animal models of neuropathic pain [48,[50][51][52] and pain conditions on human volunteers [53][54][55][56].…”

Section: Discussionmentioning

confidence: 99%

5-O-methylcneorumchromone K Exerts Antinociceptive Effects in Mice via Interaction with GABAA Receptors

Opretzka

Freitas

Santo

et al. 2021

IJMS

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The proper pharmacological control of pain is a continuous challenge for patients and health care providers. Even the most widely used medications for pain treatment are still ineffective or unsafe for some patients, especially for those who suffer from chronic pain. Substances containing the chromone scaffold have shown a variety of biological activities, including analgesic effects. This work presents for the first time the centrally mediated antinociceptive activity of 5-O-methylcneorumchromone K (5-CK). Cold plate and tail flick tests in mice showed that the 5-CK-induced antinociception was dose-dependent, longer-lasting, and more efficacious than that induced by morphine. The 5-CK-induced antinociception was not reversed by the opioid antagonist naloxone. Topological descriptors (fingerprints) were employed to narrow the antagonist selection to further investigate 5-CK’s mechanism of action. Next, based on the results of fingerprints analysis, functional antagonist assays were conducted on nociceptive tests. The effect of 5-CK was completely reversed in both cold plate and tail-flick tests by GABAA receptor antagonist bicuculline, but not by atropine or glibenclamide. Molecular docking studies suggest that 5-CK binds to the orthosteric binding site, with a similar binding profile to that observed for bicuculline and GABA. These results evidence that 5-CK has a centrally mediated antinociceptive effect, probably involving the activation of GABAergic pathways.

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“…Thus, biochemical studies are warranted to further characterize these compounds. For BZR binding, GABA A R subtype selectivity can be determined by electrophysiology to identify selective α 2,3,5 β 3 γ 2 GABA A R ligands with several clinical applications including pain [ 34 , 35 ]. For KOR agonists, G-protein biased ligands with weak effects on β-arrestin recruitment have shown promise as analgesic agents with reduced adverse side effects, such as sedation and dysphoria [ 36 ].…”

Section: Discussionmentioning

confidence: 99%

A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor

Nieman

Mian

et al. 2020

Molecules

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Analgesic and anti-inflammatory properties mediated by the κ opioid receptor (KOR) have been reported for oxadiazole imidazodiazepines. Affinities determined by radioligand competition assays of more than seventy imidazodiazepines using cell homogenates from HEK293 cells that overexpress KOR, µ opioid receptor (MOR), and δ opioid receptor (DOR) are presented. Affinities to synaptic, benzodiazepine-sensitive receptors (BZR) were determined with rat brain extract. The highest affinity for KOR was recorded for GL-I-30 (Ki of 27 nM) and G-protein recruitment was observed with an EC50 of 32 nM. Affinities for MOR and DOR were weak for all compounds. Ester and amide imidazodiazepines were among the most active KOR ligands but also competed with 3H-flunitrazepam for brain extract binding, which is mediated predominately by gamma aminobutyric acid type A receptors (GABAAR) of the α1-3β2-3γ1-2 subtypes. Imidazodiazepines with carboxylic acid and primary amide groups did not bind KOR but interacted strongly with GABAARs. Pyridine substitution reduced KOR affinity. Oxadiazole imidazodiazepines exhibited good KOR binding and interacted weakly with BZR, whereas oxazole imidazodiazepines were more selective towards BZR. Compounds that lack the imidazole moiety, the pendent phenyl, or pyridine substitutions exhibited insignificant KOR affinities. It can be concluded that a subset of imidazodiazepines represents novel KOR ligands with high selectivity among opioid receptors.

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

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

Cited by 30 publications

References 53 publications

Facilitation of Social Support through Negative Allosteric Modulation of α5-Associated GABAA Receptors: A Novel Mechanism for the Treatment of Depression, Agitation, and Aggression in the Elderly

Facilitation of Social Support through Negative Allosteric Modulation of α5-Associated GABAA Receptors: A Novel Mechanism for the Treatment of Depression, Agitation, and Aggression in the Elderly

5-O-methylcneorumchromone K Exerts Antinociceptive Effects in Mice via Interaction with GABAA Receptors

A Structure-Activity Relationship Comparison of Imidazodiazepines Binding at Kappa, Mu, and Delta Opioid Receptors and the GABAA Receptor

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