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

Jeffrey M. Witkin, Guanguan Li, Lalit K. Golani, Wenhui Xiong, Jodi L. Smith, Xingjie Ping, Farjana Rashid, Rajwana Jahan, Rok Cerne, James M. Cook, Xiaoming Jin

Research output: Contribution to journalArticle

1 Scopus citations


The imidizodiazepine, 5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f] imidazo[1,5-a][1,4]diazepin-3-yl)oxazole (KRM-II-81), is selective for α2/3-containing GABAA 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) (ED50 5 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 α1β3γ2L GABAA 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 α1His102, providing a structural rationale for its low affinity for α1-containing GABAA 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.

Original languageEnglish (US)
Pages (from-to)83-94
Number of pages12
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number1
StatePublished - Jan 2020

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

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