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首页> 外文期刊>Life sciences >A NOVEL ELECTROPHILIC HIGH AFFINITY IRREVERSIBLE PROBE FOR THE CANNABINOID RECEPTOR
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A NOVEL ELECTROPHILIC HIGH AFFINITY IRREVERSIBLE PROBE FOR THE CANNABINOID RECEPTOR

机译：大麻受体的新的高亲和力不可逆探针

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In order to explore the structural requirements for cannabinoid activity we have been involved in the design and synthesis of stereochemically defined high affinity probes for the cannabinoid receptor. This effort has involved the development of irreversible ligands which will allow us to obtain detailed information on the cannabinoid receptor active site(s). The irreversible ligands, which incorporate highly reactive functional groups in a strategic position of the ligand, may form covalent bonds with amino acid residues at the receptor active site or in the neighborhood of this site. We shall discuss the biochemical properties of one of these probes, which incorporates the electrophilic isothiocyanate group into the structure of the highly potent cannabinoid agonist (-)-1',1'-dimethylheptyl-Delta(8)-THC. This ligand, (-)-7'-isothiocyanato-1',1'-dimethylheptyl-Delta(8)-THC (7'-NCS-DMH-Delta(8)-THC), was evaluated for its affinity for cannabinoid binding sites using rat forebrain membrane preparations and found to have an apparent IC50 value of 660 pM. Incubation of the membrane preparation with a ligand concentration of five times the apparent IC50 resulted in the irreversible occupation of nearly all of the receptor specific binding sites. [References: 14]
机译：为了探索大麻素活性的结构要求，我们参与了针对大麻素受体的立体化学定义的高亲和力探针的设计和合成。这项工作涉及了不可逆配体的开发，这将使我们能够获得有关大麻素受体活性位点的详细信息。在配体的关键位置结合了高反应性官能团的不可逆配体可以与受体活性位点或该位点附近的氨基酸残基形成共价键。我们将讨论其中一种探针的生化特性，该探针将亲电异硫氰酸酯基团掺入高效大麻素激动剂（-）-1'，1'-二甲基庚基-Delta（8）-THC的结构中。评估该配体（-）-7'-isothiocyanato-1'，1'-二甲基庚基-Delta（8）-THC（7'-NCS-DMH-Delta（8）-THC）对大麻素结合的亲和力使用大鼠前脑膜制备物的位置，发现其表观IC50值为660 pM。用配体浓度为表观IC50的5倍孵育膜制剂会导致几乎所有受体特异性结合位点不可逆地被占据。 [参考：14]

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