Imidazodiazepine anticonvulsant, KRM-II-81, produces novel, non-diazepam-like antiseizure effects

Daniel E. Knutson, Jodi L. Smith, Xingjie Ping, Xiaoming Jin, Lalit K. Golani, Guanguan Li, V. V.N.Phani Babu Tiruveedhula, Farjana Rashid, Md Yeunus Mian, Rajwana Jahan, Dishary Sharmin, Rok Cerne, James M. Cook, Jeffrey M. Witkin

Research output: Contribution to journalArticlepeer-review

Abstract

The need for improved medications for the treatment of epilepsy and chronic pain is essential. Epileptic patients typically take multiple antiseizure drugs without complete seizure freedom, and chronic pain is not fully managed with current medications. A positive allosteric modulator (PAM) of α2/3-containing GABAA receptors (5-(8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazole[1,5-α][1,4]diazepin-3-yl) oxazole or KRM-II-81 (8) is a lead compound in a series of imidazodiazepines. We previously reported that KRM-II-81 produces broad-based anticonvulsant and antinociceptive efficacy in rodent models and provides a wider margin over motoric side effects than that of other GABAA receptor PAMs. The present series of experiments was designed to fill key missing gaps in prior preclinical studies assessing whether KRM-II-81 could be further differentiated from nonselective GABAA receptor PAMs using the anticonvulsant diazepam (DZP) as a comparator. In multiple chemical seizure provocation models in mice, KRM-II-81 was either equally or more efficacious than DZP. Most strikingly, KRM-II-81 but not DZP blocked the development of seizure sensitivity to the chemoconvulsants cocaine and pentylenetetrazol in seizure kindling models. These and predecessor data have placed KRM-II-81 into consideration for clinical development requiring the manufacture of kilogram amounts of good manufacturing practice material. We describe here a novel synthetic route amenable to kilogram quantity production. The new biological and chemical data provide key steps forward in the development of KRM-II-81 (8) as an improved treatment option for patients suffering from epilepsy.

Original languageEnglish (US)
Pages (from-to)2624-2637
Number of pages14
JournalACS Chemical Neuroscience
Volume11
Issue number17
DOIs
StatePublished - Sep 2 2020

Keywords

  • GABAreceptor PAMs
  • KRM-II-81
  • diazepam
  • epilepsy
  • seizure kindling
  • α2/3-containing GABAreceptors

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Cognitive Neuroscience
  • Cell Biology

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