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 = 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. 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.