Carroll F Ivy, Robinson T Philip, Brieaddy Lawrence E, Atkinson Robert N, Mascarella S Wayne, Damaj M Imad, Martin Billy R, Navarro Hernán A
Organic and Medicinal Chemistry, Research Triangle Institute, Research Triangle Park, North Carolina 27709, USA.
J Med Chem. 2007 Dec 13;50(25):6383-91. doi: 10.1021/jm0704696. Epub 2007 Nov 10.
Epibatidine analogues 3- 5, possessing the pyridine ring fused to the 2,3 position of the 7-azabicyclo[2.2.1]heptane ring, and analogue 8a, possessing a benzene ring fused to the 5,6 position, were synthesized by procedures involving key steps of trapping 2,3-pyridyne, 3,4-pyridyne, and benzyne with tert-butyl 1 H-pyrrole-1-carboxylate. Two epibatidine analogues, 6 and 7, which have the 2'-chloropyridine ring bridged to the 7-azabicyclo[2.2.1]heptane ring via a methylene group, were synthesized, where the key step was an intramolecular reductive palladium-catalyzed Heck-type coupling. Even though the conformationally restricted epibatidine analogues, 3- 7, and the benzo analogue 8a possess nAChR pharmacophore features thought to be needed for alpha(4)beta(2) binding, they all showed low affinity for nAChRs relative to epibatidine. These studies provide new information concerning the pharmacophore for nAChRs and suggest that nitrogen lone-pair directionality and steric factors may be important. Interestingly, N-methylepibatidine, prepared as a standard compound for the study of bridged analogues 6 and 7, was a potent nAChR mixed agonist antagonist.
通过涉及用叔丁基 1H - 吡咯 - 1 - 羧酸酯捕获 2,3 - 吡啶炔、3,4 - 吡啶炔和苯炔等关键步骤的方法，合成了在 7 - 氮杂双环[2.2.1]庚烷环的 2,3 位稠合有吡啶环的埃博霉素类似物 3 - 5 以及在 5,6 位稠合有苯环的类似物 8a。合成了两个埃博霉素类似物 6 和 7，它们通过亚甲基将 2'-氯吡啶环与 7 - 氮杂双环[2.2.1]庚烷环相连，其中关键步骤是分子内还原钯催化的赫克型偶联反应。尽管构象受限的埃博霉素类似物 3 - 7 和苯并类似物 8a 具有被认为是α(4)β(2)结合所需的烟碱型乙酰胆碱受体药效团特征，但相对于埃博霉素，它们对烟碱型乙酰胆碱受体均显示出低亲和力。这些研究提供了关于烟碱型乙酰胆碱受体药效团的新信息，并表明氮孤对方向性和空间因素可能很重要。有趣的是，作为研究桥连类似物 6 和 7 的标准化合物制备的 N - 甲基埃博霉素是一种有效的烟碱型乙酰胆碱受体混合激动剂拮抗剂。
