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, Y9 and YZ4, 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, YZ4 displayed favorable pharmacokinetic (PK) profiles, including high oral bioavailability and excellent brain penetration. In a POX-intoxicated mouse model, YZ4 significantly improved survival rates, alleviated seizure severity and mitigated multiorgan injury. These findings demonstrate YZ4 as a promising molecular tool for probing α7 nAChR pathophysiology and a potential therapeutic candidate for OP poisoning.
Zhang et al. (2026) studied this question.