Bioisosteres of ethyl 8-ethynyl-6-(pyridin-2-yl)-4H-benzo[f]imidazo [1,5-a][1,4]diazepine-3-carboxylate (HZ-166) as novel alpha 2,3 selective potentiators of GABA A receptors: Improved bioavailability enhances anticonvulsant efficacy

J. M. Witkin, J. L. Smith, X. Ping, S. D. Gleason, M. M. Poe, G. Li, X. Jin, J. Hobbs, J. M. Schkeryantz, J. S. McDermott, A. I. Alatorre, J. N. Siemian, J. W. Cramer, D. C. Airey, K. R. Methuku, V. V.N.P.B. Tiruveedhula, T. M. Jones, J. Crawford, M. J. Krambis, J. L. FisherJ. M. Cook, R. Cerne

Research output: Contribution to journalArticle

8 Scopus citations


HZ-166 has previously been characterized as an α2,3-selective GABA A receptor modulator with anticonvulsant, anxiolytic, and anti-nociceptive properties but reduced motor effects. We discovered a series of ester bioisosteres with reduced metabolic liabilities, leading to improved efficacy as anxiolytic-like compounds in rats. In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models. In some models we also evaluated key structural analogs. KRM-II-81 suppressed hyper-excitation in a network of cultured cortical neurons without affecting the basal neuronal activity. KRM-II-81 was active against electroshock-induced convulsions in mice, pentylenetetrazole (PTZ)-induced convulsions in rats, elevations in PTZ-seizure thresholds, and amygdala-kindled seizures in rats with efficacies greater than that of diazepam. KRM-II-81 was also active in the 6 Hz seizure model in mice. Structural analogs of KRM-II-81 but not the ester, HZ-166, were active in all models in which they were evaluated. We further evaluated KRM-II-81 in human cortical epileptic tissue where it was found to significantly-attenuate picrotoxin- and AP-4-induced increases in firing rate across an electrode array. These molecules generally had a wider margin of separation in potencies to produce anticonvulsant effects vs. motor impairment on an inverted screen test than did diazepam. Ester bioisosters of HZ-166 are thus presented as novel agents for the potential treatment of epilepsy acting via selective positive allosteric amplification of GABA A signaling through α2/α3-containing GABA receptors. The in vivo data from the present study can serve as a guide to dosing parameters that predict engagement of central GABA A receptors.

Original languageEnglish (US)
Pages (from-to)332-343
Number of pages12
StatePublished - Jul 15 2018


  • Alpha 2/3 subunit
  • Anxiety
  • Epilepsy
  • GABA-A receptors

ASJC Scopus subject areas

  • Pharmacology
  • Cellular and Molecular Neuroscience

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