title: Conformational re-analysis of (+)-meptazinol: an opioid with mixed analgesic pharmacophores.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  (+)-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol.
authors.affiliation: Department of Medicinal Chemistry, Fudan University, Shanghai 200032, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Xing-hai
authors.initials: XH
authors.lastname: Wang
authors.forename: Choi-wan
authors.initials: CW
authors.lastname: Lau
authors.forename: Yun
authors.initials: Y
authors.lastname: Tang
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xie
authors.forename: Zhui-bai
authors.initials: ZB
authors.lastname: Qiu
mesh_terms: D000701:Analgesics, Opioid / Q000737:chemistry* / Q000494:pharmacology; D008621:Meptazinol / Q000737:chemistry* / Q000494:pharmacology; D008968:Molecular Conformation; D015394:Molecular Structure; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000701:Analgesics, Opioid; D008621:Meptazinol