2. Academic Validation
  3. Discovery of Novel Antiepileptic Agents Targeting the α1β2γ2 GABAA Receptor

Discovery of Novel Antiepileptic Agents Targeting the α1β2γ2 GABAA Receptor

  • J Med Chem. 2025 Aug 28;68(16):17971-17989. doi: 10.1021/acs.jmedchem.5c01770.
Yuan Gao 1,  Amina Noraddin 1 2 3,  Xinyi Li 1,  Chengchun Zhu 1,  Yang Zhang 1 4,  Yaran Jin 1 4,  Meng Zhang 1,  Yan Yu 1,  Xiao Wang 1,  Ke Wang 1,  Ying Shi 1,  Yiping Gao 1,  Xiaoyu Liu 5,  Tianbin Liu 5,  Kai Chen 5,  Zhiyi Yu 1
Affiliations

Affiliations

  • 1 School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, China.
  • 2 Immagina Biotechnology S.r.l, Viale dell'Industria 47, 38057 Pergine Valsugana, TN, Italy.
  • 3 Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Sommarive 9, Trento 38123, Povo, Italy.
  • 4 College of Pharmacy, Shandong University of Traditional Chinese Medicine, Jinan 250355, China.
  • 5 Center for New Drug Evaluation, Shandong Academy of Pharmaceutical Sciences, Jinan 250000, China.
PMID: 40788257 DOI: 10.1021/acs.jmedchem.5c01770
Abstract

The type A γ-aminobutyric acid receptor (GABAAR) 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 GABAAR in a newly validated MQAE-based fluorescence assay. Among these, compound 10 demonstrated the highest potency, enhancing the GABAAR function by 36% at 10 μM. This activity was further confirmed by patch-clamp recordings, affording an EC50 and Emax of 1.99 μM and 80.1%, respectively. Subsequently, the antiepileptic activity of compound 10 was substantiated in zebrafish and mice models. Notably, compound 10 displayed greater efficacy than carbamazepine in both the PTZ- and KA-induced mice epilepsy models. Furthermore, compound 10 exerted negligible neuronal cytotoxicity, and possessed a favorable bioavailability and an acceptable half-life. Collectively, compound 10 represents a potent PAM of α1β2γ2 GABAAR and offers potential advantages over current therapies for the treatment of epilepsy.

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