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Epilepsia May 1, 2020; 61 (5): 914-923.

Functional characterization of the antiepileptic drug candidate, padsevonil, on GABAA receptors.

Niespodziany I , Ghisdal P , Mullier B , Wood M , Provins L , Kaminski RM , Wolff C .

OBJECTIVE: The antiepileptic drug candidate, padsevonil, is the first in a novel class of drugs designed to interact with both presynaptic and postsynaptic therapeutic targets: synaptic vesicle 2 proteins and γ-aminobutyric acid type A receptors (GABAA Rs), respectively. Functional aspects of padsevonil at the postsynaptic target, GABAA Rs, were characterized in experiments reported here. METHODS: The effect of padsevonil on GABA-mediated Cl- currents was determined by patch clamp on recombinant human GABAA Rs (α1β2γ2) stably expressed in a CHO-K1 cell line and on native GABAA Rs in cultured rat primary cortical neurons. Padsevonil selectivity for GABAA R subtypes was evaluated using a two-electrode voltage clamp on recombinant human GABAA Rs (α1-5/β2/γ2) in Xenopus oocytes. RESULTS: In recombinant GABAA Rs, padsevonil did not evoke Cl- currents in the absence of the agonist GABA. However, when co-administered with GABA at effective concentration (EC)20 , padsevonil potentiated GABA responses by 167% (EC50 138 nmol/L) and demonstrated a relative efficacy of 41% compared with zolpidem, a reference benzodiazepine site agonist. Similarly, padsevonil demonstrated GABA-potentiating activity at native GABAA Rs (EC50 208 nmol/L) in cultured rat cortical neurons. Padsevonil also potentiated GABA (EC20 ) responses in GABAA Rs expressed in oocytes, with higher potency at α1- and α5-containing receptors (EC50 295 and 281 nmol/L) than at α2- and α3-containing receptors (EC50 1737 and 2089 nmol/L). Compared with chlordiazepoxide-a nonselective, full GABAA R agonist-the relative efficacy of padsevonil was 60% for α1β2γ2, 26% for α2β2γ2, 56% for α3β2γ2, and 41% for α5β2γ2; no activity was observed at benzodiazepine-insensitive α4β2γ2 receptors. SIGNIFICANCE: Results of functional investigations on recombinant and native neuronal GABAA Rs show that padsevonil acts as a positive allosteric modulator of these receptors, with a partial agonist profile at the benzodiazepine site. These properties may confer better tolerability and lower potential for tolerance development compared with classic benzodiazepines currently used in the clinic.

PubMed ID: 32297665
PMC ID: PMC7383892
Article link: Epilepsia
Grant support: [+]
Genes referenced: gabarap

Article Images: [+] show captions

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