title: The effect of absolute configuration on activity, subtype selectivity (M3/M2) of 3α-acyloxy-6β-acetoxyltropane derivatives as muscarinic M3 receptor antagonists.
abstract: 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.
authors: Division of Chemistry, Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
authors: Zhi-Peng
authors: ZP
authors: Wang
authors: Hui-Zhong
authors: HZ
authors: Liu
authors: Liang
authors: L
authors: Zhu
authors: You-Min
authors: YM
authors: Hu
authors: Yong-Yao
authors: YY
authors: Cui
authors: Yin-Yao
authors: YY
authors: Niu
authors: Yang
authors: Y
authors: Lu
authors: Hong-Zhuan
authors: HZ
authors: Chen
mesh_terms: D000818:Animals; D005260:Female; D006168:Guinea Pigs; D006325:Heart Atria / Q000187:drug effects; D007082:Ileum / Q000187:drug effects; D008297:Male; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D043585:Receptor, Muscarinic M2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043587:Receptor, Muscarinic M3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D014326:Tropanes / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology
chemical_list: D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; D043587:Receptor, Muscarinic M3; D014326:Tropanes