2. Academic Validation
  3. Discovery of Potent and Subtype-Selective α7 nAChR Antagonists for Organophosphate Poisoning Protection

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

  • J Med Chem. 2026 Mar 12;69(5):6138-6157. doi: 10.1021/acs.jmedchem.5c03675.
Han Zhang 1 2,  Litian Jia 1 2,  Genping Xue 1 2,  Long Tian 1 2,  Zhenhai Hu 1 2,  Cheng Shi 3,  Yuanyuan Liu 1 2,  Huijian Zeng 1 2,  Liangren Zhang 3,  Qingbin Meng 1 2
Affiliations

Affiliations

  • 1 Academy of Military Medical Sciences, NO 27 Taiping Road, Beijing 100850, China.
  • 2 State Key Laboratory of National Security Specially Needed Medicines, NO 100 Yongding Road, Beijing 100039, China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, NO 38 Xueyuan Road, Beijing 100191, China.
PMID: 41774019 DOI: 10.1021/acs.jmedchem.5c03675
Abstract

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.

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