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Yun Tang - One of the best experts on this subject based on the ideXlab platform.

  • theoretical and nmr investigations on the conformations of Meptazinol hydrochloride in solution
    Molecular Simulation, 2013
    Co-Authors: Wei Li, Yun Tang, Yan Chen, Xinghai Wang, Lili Xu, Meiyan Lu, Bo Chao, Wei Fu
    Abstract:

    ( − )-Meptazinol is an analgesic with an additional acetylcholinesterase (AChE) inhibitory activity. In order to investigate the formation mechanism of its biological conformation observed in AChE-bis( − )-Meptazinol complex, two different and naturally stable conformers of ( − )-Meptazinol hydrochloride in solution were determined and identified by nuclear magnetic resonance (NMR) and molecular dynamic simulations. Moreover, ab initio calculations and NMR evidence showed the difficulties in conformer interconversion. In combination with the results of conformational comparison, it was proposed that the pharmacophoric conformer of ( − )-Meptazinol might come from the conformer with less favourable energy rather than the conformer with the lowest energy.

  • Theoretical and NMR investigations on the conformations of ( − )-Meptazinol hydrochloride in solution
    Molecular Simulation, 2013
    Co-Authors: Wei Li, Yun Tang, Yan Chen, Xinghai Wang, Lili Xu, Meiyan Lu, Bo Chao, Wei Fu
    Abstract:

    ( − )-Meptazinol is an analgesic with an additional acetylcholinesterase (AChE) inhibitory activity. In order to investigate the formation mechanism of its biological conformation observed in AChE-bis( − )-Meptazinol complex, two different and naturally stable conformers of ( − )-Meptazinol hydrochloride in solution were determined and identified by nuclear magnetic resonance (NMR) and molecular dynamic simulations. Moreover, ab initio calculations and NMR evidence showed the difficulties in conformer interconversion. In combination with the results of conformational comparison, it was proposed that the pharmacophoric conformer of ( − )-Meptazinol might come from the conformer with less favourable energy rather than the conformer with the lowest energy.

  • The Crystal Structure of a Complex of Acetylcholinesterase with a Bis-(−)-nor-Meptazinol Derivative Reveals Disruption of the Catalytic Triad
    Journal of Medicinal Chemistry, 2009
    Co-Authors: Harry M Greenblatt, Yun Tang, Wei Fu, Israel Silman, Joel L Sussman
    Abstract:

    A bis-(−)-nor-Meptazinol derivative in which the two Meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Aβ peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 A resolution. The ligand spans the active-site gorge, with one nor-Meptazinol moiety bound at the “anionic” subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440Ne2, which is hydrogen-bonded to Ser200Oγ in the native enzyme. The second nor-Meptazinol binds at the peripheral “anionic” site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(−)-nor-Meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new Meptazinol-based...

  • the crystal structure of a complex of acetylcholinesterase with a bis nor Meptazinol derivative reveals disruption of the catalytic triad
    Journal of Medicinal Chemistry, 2009
    Co-Authors: Harry M Greenblatt, Yun Tang, Wei Fu, Israel Silman, Joel L Sussman
    Abstract:

    A bis-(−)-nor-Meptazinol derivative in which the two Meptazinol rings are linked by a nonamethylene spacer is a novel acetylcholinesterase inhibitor that inhibits both catalytic activity and Aβ peptide aggregation. The crystal structure of its complex with Torpedo californica acetylcholinesterase was determined to 2.7 A resolution. The ligand spans the active-site gorge, with one nor-Meptazinol moiety bound at the “anionic” subsite of the active site, disrupting the catalytic triad by forming a hydrogen bond with His440Ne2, which is hydrogen-bonded to Ser200Oγ in the native enzyme. The second nor-Meptazinol binds at the peripheral “anionic” site at the gorge entrance. A number of GOLD models of the complex, using both native TcAChE and the protein template from the crystal structure of the bis-(−)-nor-Meptazinol/TcAChE complex, bear higher similarity to the X-ray structure than a previous model obtained using the mouse enzyme structure. These findings may facilitate rational design of new Meptazinol-based...

  • conformational re analysis of Meptazinol an opioid with mixed analgesic pharmacophores
    Acta Pharmacologica Sinica, 2006
    Co-Authors: Wei Li, Yun Tang, Xinghai Wang
    Abstract:

    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.

Zhiqi Zhao - One of the best experts on this subject based on the ideXlab platform.

  • antinociceptive effects of Meptazinol and its isomers on carrageenan induced thermal hyperalgesia in rats
    Acta physiologica Sinica, 2004
    Co-Authors: Peifen Wang, Yuqiu Zhang, Zhiqi Zhao
    Abstract:

    Using the latency of paw withdrawal (PWL) from a noxious thermal stimulus as a measure of hyperalgesia, the effects of i.p. injection of Meptazinol and its isomers, 112824 and 112825, on carrageenan-induced thermal hyperalgesia were studied in awaked carrageenan-inflamed rats. Peripheral inflammation was induced by intraplantar (i.pl.) injection of carrageenan (2 mg/100 μl) into one hindpaw in rats. Carrageenan produced marked inflammation (edema and erythema) and thermal hyperalgesia in the injected paws, which peaked at 3 h after injection and showed little change in magnitude for another 3 h. Injection of 0. 1 mg/kg Meptazinol (i.p.) at 3 h after carrageenan had no effect on the PWLs of either inflamed or non-inflamed hindpaw during the next 100 min (P0.05, n=8). At the dosage of 1 and 10 mg/kg, Meptazinol produced marked anti-nociception and anti-hyperalgesia in non-inflamed and inflamed hindpaw, respec- tively (P0.05, n=8～11). The prolonging effect of Meptazinol on PWL in inflamed hindpaw was more potent than that in non-inflamed hindpaw. Pre-administration of 1.5 mg/kg naloxone significantly antagonized Meptazinol-induced anti-nociception and anti-hyperalgesia. Intraperitoneal injection of an isomer of Meptazinol, 112825 (1.5 mg/kg), but not 112824 (1 mg/kg), markedly increased the PWL of the non-inflamed hindpaw. Nevertheles, both the isomers produced similar anti-hyperalgesic effect to that of Meptazinol (P0.05, n=8), which was completely reversed by naloxone (1.5 mg/mg). The results suggest that Meptazinol and its isomers have anti-nociceptive and anti-hyperalgesic properties with the former more potent. The effects are mainly mediated by mu opioid receptors. This study provides an important clue for extending clinical utilization of Meptazinol and its isomers.

  • inhibitory effect of intrathecal Meptazinol on carrageenan induced thermal hyperalgesia in rats
    Neuroscience Letters, 2004
    Co-Authors: Hua Zhang, Yuqiu Zhang, Zhiqi Zhao
    Abstract:

    Abstract The effect of Meptazinol in the spinal cord on carrageenan-induced hyperalgesia was investigated. The latency of paw withdrawal (PWL) to a thermal stimulus was used as an index of inflammatory hyperalgesia in awake rats. Intrathecal (i.t.) injection of 10 and 100 μg Meptazinol markedly increased the PWL of the carrageenan-injected paw (P

Wei Li - One of the best experts on this subject based on the ideXlab platform.

  • theoretical and nmr investigations on the conformations of Meptazinol hydrochloride in solution
    Molecular Simulation, 2013
    Co-Authors: Wei Li, Yun Tang, Yan Chen, Xinghai Wang, Lili Xu, Meiyan Lu, Bo Chao, Wei Fu
    Abstract:

    ( − )-Meptazinol is an analgesic with an additional acetylcholinesterase (AChE) inhibitory activity. In order to investigate the formation mechanism of its biological conformation observed in AChE-bis( − )-Meptazinol complex, two different and naturally stable conformers of ( − )-Meptazinol hydrochloride in solution were determined and identified by nuclear magnetic resonance (NMR) and molecular dynamic simulations. Moreover, ab initio calculations and NMR evidence showed the difficulties in conformer interconversion. In combination with the results of conformational comparison, it was proposed that the pharmacophoric conformer of ( − )-Meptazinol might come from the conformer with less favourable energy rather than the conformer with the lowest energy.

  • Theoretical and NMR investigations on the conformations of ( − )-Meptazinol hydrochloride in solution
    Molecular Simulation, 2013
    Co-Authors: Wei Li, Yun Tang, Yan Chen, Xinghai Wang, Lili Xu, Meiyan Lu, Bo Chao, Wei Fu
    Abstract:

    ( − )-Meptazinol is an analgesic with an additional acetylcholinesterase (AChE) inhibitory activity. In order to investigate the formation mechanism of its biological conformation observed in AChE-bis( − )-Meptazinol complex, two different and naturally stable conformers of ( − )-Meptazinol hydrochloride in solution were determined and identified by nuclear magnetic resonance (NMR) and molecular dynamic simulations. Moreover, ab initio calculations and NMR evidence showed the difficulties in conformer interconversion. In combination with the results of conformational comparison, it was proposed that the pharmacophoric conformer of ( − )-Meptazinol might come from the conformer with less favourable energy rather than the conformer with the lowest energy.

  • conformational re analysis of Meptazinol an opioid with mixed analgesic pharmacophores
    Acta Pharmacologica Sinica, 2006
    Co-Authors: Wei Li, Yun Tang, Xinghai Wang
    Abstract:

    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.

  • Conformational re-analysis of (+)-Meptazinol: an opioid with mixed analgesic pharmacophores.
    Acta Pharmacologica Sinica, 2006
    Co-Authors: Wei Li, Xinghai Wang, Yun Tang
    Abstract:

    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.

  • Investigation of the binding mode of (-)-Meptazinol and bis-Meptazinol derivatives on acetylcholinesterase using a molecular docking method.
    Journal of Molecular Modeling, 2006
    Co-Authors: Yun Tang, Wei Li, Xinghai Wang
    Abstract:

    Molecular docking has been performed to investigate the binding mode of (−)-Meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-Meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD

J W Sear - One of the best experts on this subject based on the ideXlab platform.

  • influence of Meptazinol on metabolic and hormonal responses following major surgery a comparison with morphine
    Anaesthesia, 2007
    Co-Authors: M C Allen, R K Price, R E S Bullingham, D Baldwin, R J Mcquay, H A Moore, J W Sear
    Abstract:

    Summary Opioid drugs in high doses can obtund the stress response to major surgery but only at the expense of marked cardiorespiratory depression. The postoperative hormonal response to surgical stress was measured in 20 patients undergoing hysterectomy who were given either Meptazinol 100 mg or morphine 15 mg intramuscularly at the end of the surgery. Both drugs at the doses used failed to diminish the stress response. Those patients who received Meptazinol showed elevated prolactin levels: this may be an indicator of agonist activity at the μ1, opioid receptor.

Xinghai Wang - One of the best experts on this subject based on the ideXlab platform.

  • theoretical and nmr investigations on the conformations of Meptazinol hydrochloride in solution
    Molecular Simulation, 2013
    Co-Authors: Wei Li, Yun Tang, Yan Chen, Xinghai Wang, Lili Xu, Meiyan Lu, Bo Chao, Wei Fu
    Abstract:

    ( − )-Meptazinol is an analgesic with an additional acetylcholinesterase (AChE) inhibitory activity. In order to investigate the formation mechanism of its biological conformation observed in AChE-bis( − )-Meptazinol complex, two different and naturally stable conformers of ( − )-Meptazinol hydrochloride in solution were determined and identified by nuclear magnetic resonance (NMR) and molecular dynamic simulations. Moreover, ab initio calculations and NMR evidence showed the difficulties in conformer interconversion. In combination with the results of conformational comparison, it was proposed that the pharmacophoric conformer of ( − )-Meptazinol might come from the conformer with less favourable energy rather than the conformer with the lowest energy.

  • Theoretical and NMR investigations on the conformations of ( − )-Meptazinol hydrochloride in solution
    Molecular Simulation, 2013
    Co-Authors: Wei Li, Yun Tang, Yan Chen, Xinghai Wang, Lili Xu, Meiyan Lu, Bo Chao, Wei Fu
    Abstract:

    ( − )-Meptazinol is an analgesic with an additional acetylcholinesterase (AChE) inhibitory activity. In order to investigate the formation mechanism of its biological conformation observed in AChE-bis( − )-Meptazinol complex, two different and naturally stable conformers of ( − )-Meptazinol hydrochloride in solution were determined and identified by nuclear magnetic resonance (NMR) and molecular dynamic simulations. Moreover, ab initio calculations and NMR evidence showed the difficulties in conformer interconversion. In combination with the results of conformational comparison, it was proposed that the pharmacophoric conformer of ( − )-Meptazinol might come from the conformer with less favourable energy rather than the conformer with the lowest energy.

  • conformational re analysis of Meptazinol an opioid with mixed analgesic pharmacophores
    Acta Pharmacologica Sinica, 2006
    Co-Authors: Wei Li, Yun Tang, Xinghai Wang
    Abstract:

    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.

  • Conformational re-analysis of (+)-Meptazinol: an opioid with mixed analgesic pharmacophores.
    Acta Pharmacologica Sinica, 2006
    Co-Authors: Wei Li, Xinghai Wang, Yun Tang
    Abstract:

    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.

  • Investigation of the binding mode of (-)-Meptazinol and bis-Meptazinol derivatives on acetylcholinesterase using a molecular docking method.
    Journal of Molecular Modeling, 2006
    Co-Authors: Yun Tang, Wei Li, Xinghai Wang
    Abstract:

    Molecular docking has been performed to investigate the binding mode of (−)-Meptazinol (MEP) with acetylcholinesterase (AChE) and to screen bis-Meptazinol (bis-MEP) derivatives for preferable synthetic candidates virtually. A reliable and practical docking method for investigation of AChE ligands was established by the comparison of two widely used docking programs, FlexX and GOLD. In our hands, we had more luck using GOLD than FlexX in reproducing the experimental poses of known ligands (RMSD