Design, Synthesis, and Biological Activity of 5'-Phenyl-1,2,5,6-tetrahydro-3,3'-bipyridine Analogues as Potential Antagonists of Nicotinic Acetylcholine Receptors

Authors

Yafei Jin, University of Michigan - Ann Arbor
Xiaoqin Huang, University of Kentucky
Roger L. Papke, University of Florida
Emily M. Jutkiewicz, University of Michigan - Ann Arbor
Hollis D Showalter, University of Michigan - Ann Arbor
Chang-Guo Zhan, University of KentuckyFollow

Abstract

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 (K_i = 123 nM) over the α4β2, and α7 receptors.

Document Type

Article

Publication Date

9-15-2017

Notes/Citation Information

Published in Bioorganic & Medicinal Chemistry Letters, v. 27, issue 18, p. 4350-4353.

© 2017 Elsevier Ltd. All rights reserved.

This manuscript version is made available under the CC‐BY‐NC‐ND 4.0 license https://creativecommons.org/licenses/by-nc-nd/4.0/.

The document available for download is the author's post-peer-review final draft of the article.

Digital Object Identifier (DOI)

https://doi.org/10.1016/j.bmcl.2017.08.025

Funding Information

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.

Related Content

Refer to Web version on PubMed Central for supplementary material.

Repository Citation

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.
https://uknowledge.uky.edu/ps_facpub/122