{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"submitter":["Witkin JM"],"funding":["NIDA NIH HHS"],"pagination":["83-94"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC6927408"],"repository":["biostudies-literature"],"omics_type":["Unknown"],"volume":["372(1)"],"pubmed_abstract":["The imidizodiazepine, 5-(8-ethynyl-6-(pyridin-2-yl)-4<i>H</i>-benzo[<i>f</i>]imidazo[1,5-<i>a</i>][1,4]diazepin-3-yl)oxazole (KRM-II-81), is selective for <i>?</i>2/3-containing GABA<sub>A</sub> receptors. KRM-II-81 dampens seizure activity in rodent models with enhanced efficacy and reduced motor-impairment compared with diazepam. In the present study, KRM-II-81 was studied in assays designed to detect antiepileptics with improved chances of impacting pharmaco-resistant epilepsies. The potential for reducing neural hyperactivity weeks after traumatic brain injury was also studied. KRM-II-81 suppressed convulsions in corneal-kindled mice. Mice with kainate-induced mesial temporal lobe seizures exhibited spontaneous recurrent hippocampal paroxysmal discharges that were significantly reduced by KRM-II-81 (15 mg/kg, orally). KRM-II-81 also decreased convulsions in rats undergoing amygdala kindling in the presence of lamotrigine (lamotrigine-insensitive model) (ED<sub>50</sub> = 19 mg/kg, i.p.). KRM-II-81 reduced focal and generalized seizures in a kainate-induced chronic epilepsy model in rats (20 mg/kg, i.p., three times per day). In mice with damage to the left cerebral cortex by controlled-cortical impact, enduring neuronal hyperactivity was dampened by KRM-II-81 (10 mg/kg, i.p.) as observed through in vivo two-photon imaging of layer II/III pyramidal neurons in GCaMP6-expressing transgenic mice. No notable side effects emerged up to doses of 300 mg/kg KRM-II-81. Molecular modeling studies were conducted: docking in the binding site of the <i>?</i>1<i>?</i>3<i>?</i>2L GABA<sub>A</sub> receptor showed that replacing the C8 chlorine atom of alprazolam with the acetylene of KRM-II-81 led to loss of the key interaction with <i>?</i>1His102, providing a structural rationale for its low affinity for <i>?</i>1-containing GABA<sub>A</sub> receptors compared with benzodiazepines such as alprazolam. Overall, these findings predict that KRM-II-81 has improved therapeutic potential for epilepsy and post-traumatic epilepsy. SIGNIFICANCE STATEMENT: We describe the effects of a relatively new orally bioavailable small molecule in rodent models of pharmaco-resistant epilepsy and traumatic brain injury. KRM-II-81 is more potent and generally more efficacious than standard-of-care antiepileptics. In silico docking experiments begin to describe the structural basis for the relative lack of motor impairment induced by KRM-II-81. KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy."],"journal":["The Journal of pharmacology and experimental therapeutics"],"pubmed_title":["The Positive Allosteric Modulator of <i>?</i>2/3-Containing GABA<sub>A</sub> Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury."],"pmcid":["PMC6927408"],"funding_grant_id":["R01 DA039530"],"pubmed_authors":["Li G","Rashid F","Cook JM","Jin X","Ping X","Witkin JM","Golani LK","Smith JL","Jahan R","Cerne R","Xiong W"],"additional_accession":[]},"is_claimable":false,"name":"The Positive Allosteric Modulator of <i>?</i>2/3-Containing GABA<sub>A</sub> Receptors, KRM-II-81, Is Active in Pharmaco-Resistant Models of Epilepsy and Reduces Hyperexcitability after Traumatic Brain Injury.","description":"The imidizodiazepine, 5-(8-ethynyl-6-(pyridin-2-yl)-4<i>H</i>-benzo[<i>f</i>]imidazo[1,5-<i>a</i>][1,4]diazepin-3-yl)oxazole (KRM-II-81), is selective for <i>?</i>2/3-containing GABA<sub>A</sub> receptors. KRM-II-81 dampens seizure activity in rodent models with enhanced efficacy and reduced motor-impairment compared with diazepam. In the present study, KRM-II-81 was studied in assays designed to detect antiepileptics with improved chances of impacting pharmaco-resistant epilepsies. The potential for reducing neural hyperactivity weeks after traumatic brain injury was also studied. KRM-II-81 suppressed convulsions in corneal-kindled mice. Mice with kainate-induced mesial temporal lobe seizures exhibited spontaneous recurrent hippocampal paroxysmal discharges that were significantly reduced by KRM-II-81 (15 mg/kg, orally). KRM-II-81 also decreased convulsions in rats undergoing amygdala kindling in the presence of lamotrigine (lamotrigine-insensitive model) (ED<sub>50</sub> = 19 mg/kg, i.p.). KRM-II-81 reduced focal and generalized seizures in a kainate-induced chronic epilepsy model in rats (20 mg/kg, i.p., three times per day). In mice with damage to the left cerebral cortex by controlled-cortical impact, enduring neuronal hyperactivity was dampened by KRM-II-81 (10 mg/kg, i.p.) as observed through in vivo two-photon imaging of layer II/III pyramidal neurons in GCaMP6-expressing transgenic mice. No notable side effects emerged up to doses of 300 mg/kg KRM-II-81. Molecular modeling studies were conducted: docking in the binding site of the <i>?</i>1<i>?</i>3<i>?</i>2L GABA<sub>A</sub> receptor showed that replacing the C8 chlorine atom of alprazolam with the acetylene of KRM-II-81 led to loss of the key interaction with <i>?</i>1His102, providing a structural rationale for its low affinity for <i>?</i>1-containing GABA<sub>A</sub> receptors compared with benzodiazepines such as alprazolam. Overall, these findings predict that KRM-II-81 has improved therapeutic potential for epilepsy and post-traumatic epilepsy. SIGNIFICANCE STATEMENT: We describe the effects of a relatively new orally bioavailable small molecule in rodent models of pharmaco-resistant epilepsy and traumatic brain injury. KRM-II-81 is more potent and generally more efficacious than standard-of-care antiepileptics. In silico docking experiments begin to describe the structural basis for the relative lack of motor impairment induced by KRM-II-81. KRM-II-81 has unique structural and anticonvulsant effects, predicting its potential as an improved antiepileptic drug and novel therapy for post-traumatic epilepsy.","dates":{"release":"2020-01-01T00:00:00Z","publication":"2020 Jan","modification":"2021-02-20T17:23:19Z","creation":"2021-02-20T17:23:19Z"},"accession":"S-EPMC6927408","cross_references":{"pubmed":["31694876"],"doi":["10.1124/jpet.119.260968"]}}