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 make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (Ki = 123 nM) over the α4β2, and α7 receptors.
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This research was supported in part by the National Science Foundation (NSF grant CHE-1111761), and the National Institutes of Health (NIH grants DA035552, DA032910, DA041115, GM057481, UL1TR001998, and T32-DA007268), and the University of Michigan Tobacco Research Network.
Refer to Web version on PubMed Central for supplementary material.
Jin, Yafei; Huang, Xiaoqin; Papke, Roger L.; Jutkiewicz, Emily M.; Showalter, Hollis D; and Zhan, Chang-Guo, "Design, Synthesis, and Biological Activity of 5'-Phenyl-1,2,5,6-tetrahydro-3,3'-bipyridine Analogues as Potential Antagonists of Nicotinic Acetylcholine Receptors" (2017). Pharmaceutical Sciences Faculty Publications. 122.