Discovery of Novel Antiepileptic Agents Targeting the α1β2γ2 GABA_A Receptor

The type A γ-aminobutyric acid receptor (GABA_AR) 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_AR in a newly validated MQAE-based fluorescence assay. Among these, compound 10 demonstrated the highest potency, enhancing the GABA_AR function by 36% at 10 μM. This activity was further confirmed by patch-clamp recordings, affording an EC₅₀ and E_max 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 GABA_AR and offers potential advantages over current therapies for the treatment of epilepsy.