Jin Yafei, Huang Xiaoqin, Papke Roger L, Jutkiewicz Emily M, Showalter Hollis D, Zhan Chang-Guo
Department of Medicinal Chemistry and Vahlteich Medicinal Chemistry Core, University of Michigan, Ann Arbor, MI 48109, United States.
Department of Pharmaceutical Sciences and Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, United States.
Bioorg Med Chem Lett. 2017 Sep 15;27(18):4350-4353. doi: 10.1016/j.bmcl.2017.08.025. Epub 2017 Aug 14.
Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5'-phenyl-1,2,5,6-tetrahydro-3,3'-bipyridines (3a-3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then subsequent modifications were made on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist, which is highly selective for α3β4 nAChR (K=123nM) over the α4β2 and α7 receptors.
从已知的烟碱型乙酰胆碱受体（nAChRs）非特异性激动剂（1）出发，基于合理指导的结构设计发现了一小系列5'-苯基-1,2,5,6-四氢-3,3'-联吡啶（3a - 3e），其在1的吡啶核心上引入了一个苯环。这些化合物通过在适当官能化的吡啶起始单体4上连续进行铃木偶联反应来合成，分别在3-位和5-位连接苯基和吡啶基取代基，然后对侧翼吡啶环进行后续修饰以得到目标化合物。化合物3a是一种新型拮抗剂，对α3β4 nAChR（K = 123 nM）具有高于α4β2和α7受体的高度选择性。
