Discovery of Potent and Subtype-Selective α7 nAChR Antagonists for Organophosphate Poisoning Protection

The α7 nicotinic acetylcholine receptor (α7 nAChR) is implicated in organophosphate (OP) poisoning, but the scarcity of potent and subtype-selective small-molecule antagonists has hindered the development of related therapeutic strategies. Based on previous structure-activity relationship (SAR) studies, 43 novel piperidine-spirooxadiazole derivatives were designed, synthesized and evaluated using patch-clamp electrophysiology. Two optimized compounds, <b>Y9</b> and <b>YZ4</b>, exhibited submicromolar inhibition of α7 nAChR and demonstrated high subtype-selectivity for α7 over other nAChR and muscarinic acetylcholine receptor (mAChR) subtypes. They showed robust neuroprotective effects against paraoxon (POX)-induced cytotoxicity in vitro. Notably, <b>YZ4</b> displayed favorable pharmacokinetic (PK) profiles, including high oral bioavailability and excellent brain penetration. In a POX-intoxicated mouse model, <b>YZ4</b> significantly improved survival rates, alleviated seizure severity and mitigated multiorgan injury. These findings demonstrate <b>YZ4</b> as a promising molecular tool for probing α7 nAChR pathophysiology and a potential therapeutic candidate for OP poisoning.