Xu R, Sim M K, Go M L
Department of Pharmacy, National University of Singapore, 10 Kent Ridge Crescent, Singapore 119260, Singapore.
Eur J Pharm Sci. 1999 Apr;8(1):39-47. doi: 10.1016/s0928-0987(98)00057-8.
The binding affinities of some tropinyl and piperidinyl esters for the submandibulary glands (M3/M1) and heart ventricle (M2) were determined from displacement experiments using 3H-labelled N-methylscopolamine as radioligand. The antimuscarinic activities of these esters were also evaluated on guinea pig bronchi. The esters inhibited the M3-mediated carbachol-induced contraction of the bronchial smooth muscle and a reasonable correlation was obtained between the binding affinities of the esters for the submandibulary glands (pKM3,M1) and their inhibitory activities (pIC50) on guinea pig bronchi. A promising compound, N-methylpiperidinyl cyclohexylphenylpropionate (NCPP) which combined good antimuscarinic activity (pA2=9.34) with a 20-fold selectivity at the M3/M1 receptors, was identified. Quantitative structure-activity relationships (QSAR) showed that the size of the ester was the main structural feature determining both binding affinity for the M3/M1 receptors and inhibitory activity on guinea pig bronchi. Esters with substituted acyl side chains (fewer hyperconjugable H atoms at the alpha-carbon) are generally associated with better activity and affinity.
使用3H标记的N - 甲基东莨菪碱作为放射性配体，通过置换实验测定了一些托品基和哌啶基酯对下颌下腺（M3/M1）和心室（M2）的结合亲和力。还在豚鼠支气管上评估了这些酯的抗毒蕈碱活性。这些酯抑制了M3介导的卡巴胆碱诱导的支气管平滑肌收缩，并且在酯对下颌下腺的结合亲和力（pKM3,M1）与其对豚鼠支气管的抑制活性（pIC50）之间获得了合理的相关性。鉴定出一种有前景的化合物，N - 甲基哌啶基环己基苯丙酸酯（NCPP），它具有良好的抗毒蕈碱活性（pA2 = 9.34），并且在M3/M1受体处具有20倍的选择性。定量构效关系（QSAR）表明，酯的大小是决定对M3/M1受体的结合亲和力和对豚鼠支气管的抑制活性的主要结构特征。具有取代酰基侧链的酯（α - 碳上较少的超共轭氢原子）通常具有更好的活性和亲和力。
