Discovery of Novel Thiazolo[4,5- d ]pyrimidin-7(6 H )-Ones as Extrasynaptic δ-GABA A Receptor-Preferring PAMs with Rapid Antidepressant-like Efficacy

Activation of extrasynaptic δ-GABAARs represents a promising strategy for rapid-acting antidepressant therapy in major depressive disorder (MDD). Here, we report the discovery and pharmacological characterization of a novel series of thiazolo[4,5-d]pyrimidin-7(6H)-one derivatives as potent positive allosteric modulators selective for δ-GABAARs. Systematic SAR exploration identified compound 12i as a lead candidate, which demonstrated high potency on the extrasynaptic receptor subtype (α4β3δ: 950% current enhancement at 10 μM, EC50 = 0.8 μM) while maintaining favorable modulation of synaptic subtypes. In vivo, 12i exerted rapid-acting antidepressant effects in both the mouse tail suspension test and the chronic restraint stress-induced depression model, with no addictive behaviors observed. These effects were completely abolished in δ-subunit knockout mice, confirming target engagement. Furthermore, 12i significantly enhanced NREM sleep in a p-chlorophenylalanine-induced insomnia model, highlighting potential dual efficacy in MDD with comorbid sleep disturbance. Collectively, these findings position 12i as a promising clinical candidate for next-generation rapid-acting antidepressant therapy.