文献类型：期刊文献

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

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

作者：Wei LI[1];Xing-hai WANG[1];Choi-wan LAU[2];Yun TANG[1,3];Qiong XIE[1];Zhui-bai QIU[1]

机构：[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

年份：2006

卷号：27

期号：9

起止页码：1247

中文期刊名：Acta Pharmacologica Sinica

外文期刊名：中国药理学报（英文版）

收录：CSTPCD;;Scopus;CSCD:【CSCD2011_2012】；PubMed;

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

语种：英文

中文关键词：（＋）meptazinol; opioid analgesics; arylpiperidines; Conformational Analysis, pharmacophore.

外文关键词：（＋）meptazinol; opioid analgesics; arylpiperidines; Conformational Analysis, pharmacophore.

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.