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

Bioorg Med Chem Lett. 2017 Sep 15;27(18):4350-4353. doi: 10.1016/j.bmcl.2017.08.025. Epub 2017 Aug 14.

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=123nM) over the α4β2 and α7 receptors.

Keywords: Acetylcholine receptor; Antagonist design; Nicotine; Organic synthesis; Selective antagonist.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Nicotinic Antagonists / chemical synthesis
  • Nicotinic Antagonists / chemistry
  • Nicotinic Antagonists / pharmacology*
  • Pyridines / chemical synthesis
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Rats
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship

Substances

  • Nicotinic Antagonists
  • Pyridines
  • Receptors, Nicotinic
  • pyridine