Design, synthesis, and biological activity of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridine analogues as potential antagonists of nicotinic acetylcholine receptors

Yafei Jin, Xiaoqin Huang, Roger L. Papke, Emily M. Jutkiewicz, Hollis D. Showalter, Chang Guo Zhan

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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

Original languageEnglish
Pages (from-to)4350-4353
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Volume27
Issue number18
DOIs
StatePublished - 2017

Bibliographical note

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. We thank Clare Stokes for conducting the oocyte experiments.

Publisher Copyright:
© 2017 Elsevier Ltd

Keywords

  • Acetylcholine receptor
  • Antagonist design
  • Nicotine
  • Organic synthesis
  • Selective antagonist

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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