The absolute configuration plays an important role in muscarinic activity of BGT-A and its analogs.
Both enantiomers of 2, 3, and 4, three bioactive analogs of muscarinic agonist BGT-A were prepared respectively and underwent functional studies and radioreceptor binding assays. 6S enantiomers of 2, 3, and 4 showed obvious muscarinic activity, while 6R ones elicited little muscarinic activity by functional studies. Besides, the affinity of 6S enantiomers of 2, 3, and 4 was greatly larger than that of their 6R enantiomers respectively. All these pharmacological results indicated the 6S configuration was beneficial for the active BGT-A analogs to bind with the muscarinic receptors. The finding was in good agreement with our previous SAR study to BGT-A and its active analogs by computational approach. The understanding to the relationship between muscarinic activity and absolute configuration will provide the basis for successive screening of BGT-A analogs as effective muscarinic agonists or antagonists in clinical use.
Niu
Yin-Yao
YY
Division of Chemistry, Department of Pharmacy, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
Zhu
Liang
L
Cui
Yong-Yao
YY
Liu
Hui-Zhong
HZ
Chen
Hong-Zhuan
HZ
Lu
Yang
Y
D000818:Animals; D005260:Female; D006168:Guinea Pigs; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018482:Muscle, Skeletal / Q000737:chemistry; D011817:Rabbits; D051381:Rats; D011976:Receptors, Muscarinic / Q000187:drug effects / Q000378:metabolism; D013237:Stereoisomerism; D013363:Submandibular Gland / Q000378:metabolism; D014326:Tropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism
D018721:Muscarinic Agonists; D011976:Receptors, Muscarinic; D014326:Tropanes; C027863:bao gong teng A