Functional characterization of the antiepileptic drug candidate, padsevonil, on GABAAreceptors
| العنوان: | Functional characterization of the antiepileptic drug candidate, padsevonil, on GABAAreceptors |
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| المؤلفون: | Isabelle Niespodziany, Christian Wolff, Philippe Ghisdal, Rafal M. Kaminski, Laurent Provins, Brice Mullier, Martyn Wood |
| المصدر: | Epilepsia |
| بيانات النشر: | Wiley, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Agonist, SV2 proteins, Zolpidem, Patch-Clamp Techniques, Allosteric modulator, medicine.drug_class, CHO Cells, Pharmacology, Receptors, Presynaptic, patch clamp, Partial agonist, Xenopus laevis, 03 medical and health sciences, Cricetulus, 0302 clinical medicine, Postsynaptic potential, drug‐resistant epilepsy, Thiadiazoles, medicine, Animals, Humans, Patch clamp, Rats, Wistar, Receptor, Neurons, GABAA receptor, Chemistry, Imidazoles, Synaptic Potentials, Receptors, GABA-A, Pyrrolidinones, Recombinant Proteins, 030104 developmental biology, nervous system, Neurology, Full‐length Original Research, Oocytes, Anticonvulsants, Female, Neurology (clinical), benzodiazepine, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | 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. |
| تدمد: | 1528-1167 0013-9580 |
| DOI: | 10.1111/epi.16497 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b2a2def8c8c74c0f16238518f4b5ac4b https://doi.org/10.1111/epi.16497 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b2a2def8c8c74c0f16238518f4b5ac4b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15281167 00139580 |
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| DOI: | 10.1111/epi.16497 |