Division of Chemistry, Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Bioorg Med Chem. 2013 Mar 1;21(5):1234-9. doi: 10.1016/j.bmc.2012.12.052. Epub 2013 Jan 9.
Both enantiomers of 3α-acyloxy-6β-acetoxyltropane derivatives 1-4 were prepared respectively and underwent functional studies and radioreceptor binding assays. 6S Enantiomers showed obvious muscarinic M3, M2 antagonistic activity, while the 6R ones elicited little muscarinic activity by functional studies. Besides, the affinity of 6S enantiomers to muscarinic M3 receptors of rat submandibulary gland, M2 receptors of rat left atria was much larger than that of corresponding 6R enantiomers. All these pharmalogical results indicated 6S configuration was favorable for 3α-acyloxy-6β-acetoxyltropane derivatives to bind with muscarinic M3 or M2 receptors and elicited antagonistic activity. Furthermore, the muscarinic M3 activity and subtype selectivity (M3/M2) of 6S enantiomers could be improved by increasing the electron density of carbonyl oxygen or introducing methylene group between the carbonyl and phenyl ring in C-3α position. Understanding the effect of absolute configuration on activity, subtype selectivity (M3/M2) of 3α-acyloxy-6β-acetoxyltropane derivatives will provide the clues for designing muscarinic M3 antagonists with high activity and low side effects or toxicity.
分别制备了 3α-acyloxy-6β-acetoxyltropane 衍生物 1-4 的对映异构体，并进行了功能研究和放射受体结合测定。6S 对映异构体表现出明显的毒蕈碱 M3、M2 拮抗活性，而 6R 对映异构体通过功能研究引起的毒蕈碱活性很小。此外，6S 对映异构体对大鼠颌下腺毒蕈碱 M3 受体、大鼠左心房 M2 受体的亲和力明显大于相应的 6R 对映异构体。所有这些药理结果表明，6S 构型有利于 3α-acyloxy-6β-acetoxyltropane 衍生物与毒蕈碱 M3 或 M2 受体结合并发挥拮抗活性。此外，通过增加羰基氧的电子密度或在 C-3α 位的羰基和苯环之间引入亚甲基，可以提高 6S 对映异构体的毒蕈碱 M3 活性和亚型选择性（M3/M2）。了解绝对构型对活性、毒蕈碱 M3 衍生物亚型选择性（M3/M2）的影响，将为设计具有高活性、低副作用或毒性的毒蕈碱 M3 拮抗剂提供线索。
