To further investigate the analgesic pharmacophore of (+)-meptazinol.
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.
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.
(+)-meptazinol was suggested to be an opioid with mixed analgesic pharmacophores, which may account for the complicated pharmacological properties of meptazinol.
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Project supported by the National Natural Science Foundation of China (No 30271539, 2003-2005).
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Li, W., Wang, X., Lau, C. et al. Conformational re-analysis of (+)-meptazinol: an opioid with mixed analgesic pharmacophores. Acta Pharmacol Sin 27, 1247–1252 (2006). https://doi.org/10.1111/j.1745-7254.2006.00375.x
- opioid analgesics
- conformational analysis