吲哚磺酰胺类化合物作为大麻素受体负变构调节剂的研发。
Development of indole sulfonamides as cannabinoid receptor negative allosteric modulators.
作者信息
Greig Iain R, Baillie Gemma L, Abdelrahman Mostafa, Trembleau Laurent, Ross Ruth A
机构信息
Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK.
Kosterlitz Centre for Therapeutics, Institute of Medical Sciences, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, Scotland, UK; Department of Pharmacology and Toxicology, University of Toronto and Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, Ontario M5S 1A8, Canada.
出版信息
Bioorg Med Chem Lett. 2016 Sep 15;26(18):4403-4407. doi: 10.1016/j.bmcl.2016.08.018. Epub 2016 Aug 6.
Existing CB1 negative allosteric modulators (NAMs) fall into a limited range of structural classes. In spite of the theoretical potential of CB1 NAMs, published in vivo studies have generally not been able to demonstrate the expected therapeutically-relevant CB1-mediated effects. Thus, a greater range of molecular tools are required to allow definitive elucidation of the effects of CB1 allosteric modulation. In this study, we show a novel series of indole sulfonamides. Compounds 5e and 6c (ABD1075) had potencies of 4 and 3nM respectively, and showed good oral exposure and CNS penetration, making them highly versatile tools for investigating the therapeutic potential of allosteric modulation of the cannabinoid system.
现有的CB1负变构调节剂（NAMs）属于有限的结构类别。尽管CB1 NAMs具有理论潜力，但已发表的体内研究通常无法证明预期的与治疗相关的CB1介导的效应。因此，需要更多种类的分子工具来明确阐明CB1变构调节的作用。在本研究中，我们展示了一系列新型的吲哚磺酰胺。化合物5e和6c（ABD1075）的效力分别为4 nM和3 nM，并表现出良好的口服暴露和中枢神经系统渗透性，使其成为研究大麻素系统变构调节治疗潜力的高度通用工具。
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