Abstract
7α-Phenyl-6α,14α-endo-etheno-tetrahydrothebaine is an analogue of morphine but with much weaker affinity and efficacy to opioid receptors. Three compounds with o-, m- and p-amino substitution on its 7α-phenyl group were designed and synthesized to evaluate their κ-opioid receptor agonistic activity and antinociceptive effect. The introduction of amino group greatly increased the binding activity to κ-opioid receptor but only compound with p-substitution showed agonistic activity with potency similar to the marketed κ agonist butorphanol. In vivo antinociceptive test showed that compound with p-amino substitution displayed highest antinociceptive activity while compounds with o-, m-amino substitution showed partial or little analgesia effects. All these data indicate that p-amino substitution conferred κ agonist activity, suggesting that 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaines with a p-amino substitution may contain a novel pharmacophore component and could be considered as a leading compound for novel antinociceptive agents.
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Acknowledgments
This work was supported by National Natural Science foundation of China (No 30672442), National Great Basic Science Project (2010CB529806); Shanghai Municipal Commission of Education Foundation (No 05BZ14); Innovation Fund for Graduate Students of Fudan University (2006-2007); Shanghai Natural Science Foundation 08ZR1401500; Doctoral Fund of the Ministry of Education of China 20070246088.
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Hong Qi and Wei Li contribute equally to this work.
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Qi, H., Li, W., Qiu, Y. et al. Synthesis and evaluation of κ-opioid receptor agonistic activity and antinociceptive effect of novel morphine analogues, 7α-phenyl-6α,14α-endo-etheno-tetrahydrothebaine with substituted o-, m- and p-amino group. Med Chem Res 20, 1364–1370 (2011). https://doi.org/10.1007/s00044-010-9471-6
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DOI: https://doi.org/10.1007/s00044-010-9471-6