Diazaspirocyclic compounds as selective ligands for the α4β2 nicotinic acetylcholine receptor

Bioorg Med Chem Lett. 2012 Aug 1;22(15):5089-92. doi: 10.1016/j.bmcl.2012.05.108. Epub 2012 Jun 13.

Abstract

Diazaspirocyclic ligands have been synthesized in four steps as selective α4β2 nicotinic acetylcholine receptor antagonists. Structural assignment of 1-(pyridin-3-yl)-2-spiropyrrolidino-3,2'-1-azabiclo[2.2.1]heptane 2, was confirmed using a combination of NMR experiments on a key intermediate, spirolactam 9. All three target compounds synthesized in this diazaspirocyclic series exhibited high affinity (K(i)<35 nM) at the human α4β2 nAChR subtype, and very low affinity for the human α7, α3β4 (ganglion) and α1β1γδ (muscle) subtypes (K(i)>500 nM).

MeSH terms

  • Aza Compounds / chemistry*
  • Heptanes / chemistry
  • Humans
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Nicotinic Antagonists / chemical synthesis
  • Nicotinic Antagonists / chemistry*
  • Nicotinic Antagonists / metabolism
  • Protein Binding
  • Protein Isoforms / antagonists & inhibitors
  • Protein Isoforms / metabolism
  • Receptors, Nicotinic / chemistry*
  • Receptors, Nicotinic / metabolism
  • Spiro Compounds / chemical synthesis
  • Spiro Compounds / chemistry*
  • Spiro Compounds / metabolism

Substances

  • Aza Compounds
  • Heptanes
  • Ligands
  • Nicotinic Antagonists
  • Protein Isoforms
  • Receptors, Nicotinic
  • Spiro Compounds
  • nicotinic receptor alpha4beta2