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Aim:To further investigate the analgesic pharmacophore of(+)-meptazinol.Methods:Two different opioid pharmacophores,Pharm-Ⅰ and Pharm-Ⅱ,were es-tablished from structures of nine typical opiates and meperidine by using molecu-lar modeling approaches according to their different structure activity relation-ship properties.They were further validated by a set of conformationally con-strained arylpiperidines.Two conformers of(+)-meptazinol(Conformer-Ⅰ and Con-former-Ⅱ)detected in solution were then fitted into the pharmacophores,respectively,by Fit Atoms facilities available in SYBYL,a computational modelingtool kit for molecular design and analysis.Results:Conformer-Ⅰ fit Pharm-Ⅰ fromtypical 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 statebetween the two established pharmacophores.Unlike typical analgesics derivedfrom 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 ordinaryconditions based on our NMR results.Conclusion:(+)-meptazinol was suggestedto be an opioid with mixed analgesic pharmacophores,which may account for thecomplicated pharmacological properties of meptazinol.
Aim: To further investigate the analgesic pharmacophore of (+) - meptazinol. Methods: Two different opioid pharmacophores, Pharm-I and Pharm-II, were es tablished from structures of nine typical opiates and meperidine by using molecular- to their different structure activity relation-ship properties. They were further validated by a set of conformationally con-strained arylpiperidines. Two conformers of (+) - meptazinol (Conformer-I and Con-former-II) detected in solution were then fitted into the pharmacophores, respectively, by Fit Atoms facilities available in SYBYL, a computational modelingtool kit for molecular design and analysis. Results: Conformer-I fit Pharm-I fromtypical opiates well. Convergent-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 statebetween the two established pharmacophores .Unlike typical analgesi cs derivedfrom 4-aryl piperidine (eg, meperidine) with one conformer absolutely overwhelming, the (+) - meptazinol exists in two conformers with similar in in solution. Both further, 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 controlled pharmacological properties of meptazinol.