Benzodiazepines (BDZs) act on the gamma-amino-butyric acid A (GABAA) receptor and potentiate the influx of chloride ions via ion channels, imparting a hyperpolarized state to the neuron. The pharmacological action exerted by a BZD is dependent on the discrete subunits of the receptor complex. Convergent evidence from transgenic animals and molecules with selectivity for the proteins required for ligand-gating has suggested that α1 comprised GABAA receptors mediate tolerance and sedative/ataxic effects of drugs whereas α2 and α 3 comprised GABAA receptors mediate anticonvulsant effects of drugs distinct from sedative/ataxic effects. A compelling clinical opportunity exists in the development of α1-sparing subtype-selective GABAA receptor ligands. These ligands are expected to result in superior treatments for seizures and anxiety without causing amnesia and ataxia, or the propensity for addiction/dependence. The ligand HZ-166 is an α2/α3- subtype selective imidazobenzodiazepine that has been reported to effect anticonvulsant activity at non-motor-impairing doses in both mice (maximal electroshock, and PTZ) and rats (maximal electroshock, PTZ, and hippocampal kindling). However the ester functionality of HZ-166 is metabolically labile and results in low bioavailability in the CNS. In an effort to improve metabolic stability, the ester function was replaced with the more stable oxazole bioisostere (KRM-II-81). In the present study, we evaluated the anticonvulsant effects KRM-II-81 across several rodent models of convulsions. 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. 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 spikes across an electrode array. Ester bioisosteres of HZ-166 are thus presented as novel agents for the potential treatment of epilepsy, acting via selective positive allosteric amplification of GABAA signaling via α2/α3-containing GABAA receptors.

Novel imidazobenzodiazepine GABAA receptor α2/α3 selective PAM for the treatment of refractory/resistance epilepsy

2019 Spring National Meeting

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