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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects
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Truncated G protein-coupled mu opioid receptor MOR-1 splice variants are targets for highly potent opioid analgesics lacking side effects

机译：截短的G蛋白偶联mu阿片受体MOR-1剪接变体是无副作用的高效阿片类镇痛药的目标

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摘要

Pain remains a pervasive problem throughout medicine, transcending all specialty boundaries. Despite the extraordinary insights into pain and its mechanisms over the past few decades, few advances have been made with analgesics. Most pain remains treated by opiates, which have significant side effects that limit their utility. We now describe a potent opiate analgesic lacking the traditional side effects associated with classical opiates, including respiratory depression, significant constipation, physical dependence, and, perhaps most important, reinforcing behavior, demonstrating that it is possible to dissociate side effects from analgesia. Evidence indicates that this agent acts through a truncated, six-transmem-brane variant of the G protein-coupled mu opioid receptor MOR-1. Although truncated splice variants have been reported for a number of G protein-coupled receptors, their functional relevance has been unclear. Our evidence now suggests that truncated variants can be physiologically important through heterodimerization, even when inactive alone, and can comprise new therapeutic targets, as illustrated by our unique opioid analgesics with a vastly improved pharmacological profile.
机译：在整个医学领域，疼痛仍然是一个普遍存在的问题，超越了所有专业领域。尽管在过去的几十年中对疼痛及其机理有非凡的见解，但止痛药的进展很少。阿片类药物仍然可以治疗大多数疼痛，而阿片类药物具有明显的副作用，限制了其效用。现在我们描述一种有效的阿片类镇痛药，其缺乏与传统阿片类药物相关的传统副作用，包括呼吸抑制，严重便秘，身体依赖性以及最重要的强化行为，这表明有可能使镇痛的副作用消失。有证据表明，该药物通过G蛋白偶联的μ阿片样物质受体MOR-1的截短的六跨膜变体起作用。尽管已经报道了许多G蛋白偶联受体的剪接剪接变体，但它们的功能相关性尚不清楚。现在，我们的证据表明，即使单独失活，截短的变体通过异二聚体在生理上也很重要，并且可以包含新的治疗靶标，正如我们独特的阿片类镇痛药具有明显改善的药理作用所说明的那样。

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  • 作者

    Susruta Majumdar; Steven Grinnell; Valerie Le Rouzic; Maxim Burgman; Lisa Polikar; Michael Ansonoff; John Pintar; Ying-Xian Pan; Gavril W. Pasternak;

  • 作者单位

    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, NJ 08854;

    Department of Neuroscience and Cell Biology, Robert Wood Johnson Medical School, Piscataway, NJ 08854;

    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

    Molecular Pharmacology and Chemistry Program and Department of Neurology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065;

  • 收录信息 美国《科学引文索引》(SCI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

    opiate receptor; rewarding behavior; kappa_3 receptor;

    机译：阿片受体;奖励行为;kappa_3受体;

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