XB-ART-61494
J Med Chem
2025 Jul 14;6815:15910-15932. doi: 10.1021/acs.jmedchem.5c00903.
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Novel 2-(2-Thienyl)-thiazolo[4,5-d]pyrimidin-7(6H)-ones Binding β+/α- Subunit Interface as GABAAR Positive Allosteric Modulator for the Treatment of Status Epilepticus in Mouse.
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Status epilepticus (SE), a life-threatening neurological emergency, is primarily treated with benzodiazepines (BZDs), which act as positive allosteric modulators (PAMs) of γ2-containing GABAA receptors (GABAARs). However, their efficacy diminishes due to γ2 subunit internalization, leading to pharmaco-resistance. In this manuscript, a series of 2-(2-thienyl)-thiazolo[4,5-d]pyrimidin-7(6H)-one derivatives were designed and evaluated using two-electrode voltage clamp in Xenopus oocytes expressing α1β2 GABAARs. We identified (S)-9d as a potent α1β2γ2 subtype PAM, showing 13-fold potentiation at 10 μM (EC50: 0.9 μM in oocytes, 0.2 μM in CHO cells) as well as α1β2 (EC50 = 1.3 μM, 1700% enhancement, in oocytes). Molecular docking and mutagenesis revealed (S)-9d binds to a distinct β+/α- interface of α1β2 GABAARs. In SE mouse models, (S)-9d (5-30 mg/kg) significantly suppressed seizure progression and reduced delayed mortality, outperforming diazepam. This study establishes a promising strategy for refractory SE to overcome BZD limitations.
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