Synthesis and activity of substituted heteroaromatics as positive allosteric modulators for α4β2α5 nicotinic acetylcholine receptors

Bioorg Med Chem Lett. 2014 Jan 15;24(2):674-8. doi: 10.1016/j.bmcl.2013.11.049. Epub 2013 Nov 28.

Abstract

The design and synthesis of a series of substituted heteroaromatic α4β2α5 positive allosteric modulators is reported. The optimization and development of the heteroaromatic series was carried out from NS9283, and several potent analogues, such as 3-(5-(pyridin-3-yl)-2H-tetrazol-2-yl)benzonitrile (5k) and 3,3'-(2H-tetrazole-2,5-diyl)dipyridine (12 h) with good in vitro efficacy were discovered.

Keywords: Positive allosteric modulators; Substituted heteroaromatics; α4β2α5.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Allosteric Regulation / drug effects
  • Allosteric Regulation / physiology
  • Animals
  • HEK293 Cells
  • Humans
  • Mice
  • Nicotinic Agonists / chemical synthesis*
  • Nicotinic Agonists / pharmacology
  • Nicotinic Antagonists / chemical synthesis*
  • Nicotinic Antagonists / pharmacology
  • Oxadiazoles / chemical synthesis
  • Oxadiazoles / pharmacology
  • Pyridines / chemical synthesis
  • Pyridines / pharmacology
  • Receptors, Nicotinic / physiology*
  • Structure-Activity Relationship

Substances

  • 3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile
  • Nicotinic Agonists
  • Nicotinic Antagonists
  • Oxadiazoles
  • Pyridines
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2
  • nicotinic receptor alpha5 subunit, human