Conformational re-analysis of(+)-meptazinol:an opioid with mixed anal-gesic pharmacophores  

作　　者：Wei LI Xing-hai WANG Choi-wan LAU Yun TANG Qiong XIE Zhui-bai QIU 

机构地区：[1]Department of Medicinal Chemistry [2]NMR Laboratory, School of Pharmacy, Fudan University, Shanghai 200032, China [3]School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China

出　　处：《Acta Pharmacologica Sinica》2006年第9期1247-1252,共6页中国药理学报（英文版）

基　　金：Project supported by the National Natural Science Foundation of China(№30271539,2003-2005).

摘　　要：Aim： To further investigate the analgesic pharmacophore of （＋）-meptazinol. Methods： Two different opioid pharmacophores, Pharm-Ⅰ and Pharm-Ⅱ, were established from structures of nine typical opiates and meperidine by using molecular modeling approaches according to their different structure activity relationship properties. They were further validated by a set of conformationally constrained arylpiperidines. Two conformers of （＋）-meptazinol （Conformer-Ⅰ and Conformer-Ⅱ） detected in solution were then fitted into the pharmacophores, respectively, by Fit Atoms facilities available in SYBYL, a computational modeling tool kit for molecular design and analysis. Results： Conformer-Ⅰ fit Pharm-Ⅰ from typical opiates well. However, Conformer-Ⅱ fit none of these pharmacophores. Instead, it was found to be similar to another potent analgesic, benzofuro[2,3-c] pyridin-6-ol, whose pharmacophore was suggested to hold the transitional state between the two established pharmacophores. Unlike typical analgesics derived from 4-aryl piperidine （eg, meperidine） with one conformer absolutely overwhelming, the （＋）-meptazinol exists in two conformers with similar amounts in solution. Furthermore, both conformers can not transform to each other freely in ordinary conditions based on our NMR results. Conclusion： （＋）-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol.Aim： To further investigate the analgesic pharmacophore of （＋）-meptazinol. Methods： Two different opioid pharmacophores, Pharm-Ⅰ and Pharm-Ⅱ, were established from structures of nine typical opiates and meperidine by using molecular modeling approaches according to their different structure activity relationship properties. They were further validated by a set of conformationally constrained arylpiperidines. Two conformers of （＋）-meptazinol （Conformer-Ⅰ and Conformer-Ⅱ） detected in solution were then fitted into the pharmacophores, respectively, by Fit Atoms facilities available in SYBYL, a computational modeling tool kit for molecular design and analysis. Results： Conformer-Ⅰ fit Pharm-Ⅰ from typical opiates well. However, Conformer-Ⅱ fit none of these pharmacophores. Instead, it was found to be similar to another potent analgesic, benzofuro[2,3-c] pyridin-6-ol, whose pharmacophore was suggested to hold the transitional state between the two established pharmacophores. Unlike typical analgesics derived from 4-aryl piperidine （eg, meperidine） with one conformer absolutely overwhelming, the （＋）-meptazinol exists in two conformers with similar amounts in solution. Furthermore, both conformers can not transform to each other freely in ordinary conditions based on our NMR results. Conclusion： （＋）-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol.

关 键 词：（＋）meptazinol opioid analgesics arylpiperidines Conformational Analysis  pharmacophore. 

分 类 号：R971.1[医药卫生—药品]