Discovery of Novel Antiepileptic Agents Targeting the α1β2γ2 GABA<sub>A</sub> Receptor
The type A γ-aminobutyric acid receptor (GABA<sub>A</sub>R) has been explored as a prime antiepileptic target. Herein, we designed and synthesized a series of purine-containing derivatives and further evaluated their efficacies as positive allosteric modulators (PAMs) of α1β2γ2 GABA<sub>A</sub>R in a newly validated MQAE-based fluorescence assay. Among these, compound <b>10</b> demonstrated the highest potency, enhancing the GABA<sub>A</sub>R function by 36% at 10 μM. This activity was further confirmed by patch-clamp recordings, affording an EC<sub>50</sub> and <i>E</i><sub>max</sub> of 1.99 μM and 80.1%, respectively. Subsequently, the antiepileptic activity of compound <b>10</b> was substantiated in zebrafish and mice models. Notably, compound <b>10</b> displayed greater efficacy than carbamazepine in both the PTZ- and KA-induced mice epilepsy models. Furthermore, compound <b>10</b> exerted negligible neuronal cytotoxicity, and possessed a favorable bioavailability and an acceptable half-life. Collectively, compound <b>10</b> represents a potent PAM of α1β2γ2 GABA<sub>A</sub>R and offers potential advantages over current therapies for the treatment of epilepsy.
Authors
- Zhiyi Yu (ORCID: https://orcid.org/0000-0001-6227-0610)
- Yaqi Jin (ORCID: https://orcid.org/0000-0002-0076-9579)
- Tianbin Liu
- Yuan Gao (ORCID: https://orcid.org/0000-0003-3777-140X)
- Chengchun Zhu
- Yiping Gao (ORCID: https://orcid.org/0000-0003-4509-3012)
- Xiao Wang (ORCID: https://orcid.org/0000-0002-3090-9894)
- Ke Wang (ORCID: https://orcid.org/0000-0002-9445-2168)
- Xinyi Li (ORCID: https://orcid.org/0000-0002-3558-3977)
- Yan Yu (ORCID: https://orcid.org/0000-0002-7045-0459)
- Meng Zhang (ORCID: https://orcid.org/0000-0002-5657-923X)
- Kai Chen (ORCID: https://orcid.org/0000-0002-8647-1182)
- Xiaoyu Liu (ORCID: https://orcid.org/0000-0001-5259-7038)
- Ying Shi (ORCID: https://orcid.org/0000-0002-8509-3503)
- Yang Zhang (ORCID: https://orcid.org/0000-0001-7490-8343)
- Amina Noraddin
Institutions
- Center for Drug Evaluation and Research (US)
- Shandong University of Traditional Chinese Medicine (CN)
- Shandong University (CN)
- University of Trento (IT)
- Sogin (Italy) (IT)
- Shandong Academy of Pharmaceutical Sciences (CN)
Publication Details
- Journal
- Journal of Medicinal Chemistry
- Published
- 2025-08-11
- DOI
- https://doi.org/10.1021/acs.jmedchem.5c01770
- Citations
- 2
- Primary Topic
- Neuroscience and Neuropharmacology Research
- Type
- article
- Field-Weighted Citation Impact
- 1.82
Funders
- Shandong University
- National Natural Science Foundation of China
- Natural Science Foundation of Shandong Province
- Taishan Scholar Project of Shandong Province