Preparation and characterization of N-(3-pyridinyl) spirocyclic diamines as ligands for nicotinic acetylcholine receptors

Bioorg Med Chem Lett. 2009 Mar 15;19(6):1682-5. doi: 10.1016/j.bmcl.2009.01.099. Epub 2009 Feb 4.

Abstract

Several N-pyridin-3-yl spirobicyclic diamines, designed as conformationally restricted analogs of tebanicline (ABT-594), were synthesized as novel ligands for nicotinic acetylcholine receptors (nAChR). The spirocyclic compounds exhibited weaker binding affinity, than other constrained analogs in accord with a pharmacophore model. Nevertheless, some (1a, 1b) possessed (partial) agonist potencies comparable to nicotine at the alpha4beta2 subtype, but with greatly improved selectivity relative to the alpha3beta4* nAChR.

MeSH terms

  • Animals
  • Azetidines / chemical synthesis*
  • Azetidines / pharmacology
  • Chemistry, Pharmaceutical / methods*
  • Diamines / chemistry*
  • Drug Design
  • Humans
  • Kinetics
  • Ligands
  • Models, Chemical
  • Molecular Conformation
  • Pyridines / chemical synthesis*
  • Pyridines / pharmacology
  • Rats
  • Receptors, Nicotinic / chemistry*
  • Structure-Activity Relationship

Substances

  • 5-(2-azetidinylmethoxy)-2-chloropyridine
  • Azetidines
  • Diamines
  • Ligands
  • Pyridines
  • Receptors, Nicotinic