In this manuscript, we report a series of chiral 6-azaspiro[2.5]octanes and related spirocycles as highly potent and selective antagonists of the muscarinic acetylcholine receptor subtype 4 (mAChR₄). Chiral separation and subsequent X-ray crystallographic analysis of early generation analogs revealed the R enantiomer to possess excellent human and rat M₄ potency, and further structure–activity relationship (SAR) studies on this chiral scaffold led to the discovery of VU6015241 (compound 19). Compound 19 is characterized by high M₄ potency and selectivity across multiple species, excellent aqueous solubility, and moderate brain exposure in rodents after intraperitoneal administration.

_{在这份手稿中，我们报告了一系列手性 6-氮杂螺[2.5]辛烷和相关螺环作为毒蕈碱乙酰胆碱受体亚型 4 (mAChR 4} )的高效和选择性拮抗剂。早期类似物的手性分离和随后的 X 射线晶体学分析表明，R对映异构体具有出色的人类和大鼠 M ₄效力，并且对该手性支架的进一步构效关系 (SAR) 研究导致发现了 VU6015241（化合物19）。化合物19的特点是高 M ₄对多个物种的效力和选择性，优异的水溶性，以及腹腔内给药后啮齿动物的适度脑暴露。