2-(Arylmethyl)-3-substituted quinuclidines as selective alpha 7 nicotinic receptor ligands

Bioorg Med Chem Lett. 2005 Apr 15;15(8):2073-7. doi: 10.1016/j.bmcl.2005.02.045.

Abstract

A series of 2-(arylmethyl)-3-substituted quinuclidines was developed as alpha7 neuronal nicotinic acetylcholine receptor (nAChR) agonists based on a putative pharmacophore model. The series is highly selective for the alpha7 over other nAChRs (e.g., the alpha4beta2 of the CNS, and the muscle and ganglionic subtypes) and is functionally tunable at alpha7. One member of the series, (+)-N-(1-azabicyclo[2.2.2]oct-3-yl)benzo[b]furan-2-carboxamide (+)-8l), has potent agonistic activity for the alpha7 nAChR (EC(50)=33nM, I(max)=1.0), at concentrations below those that result in desensitization.

MeSH terms

  • Animals
  • Cell Line
  • Humans
  • Ligands
  • Quinuclidines / chemistry*
  • Quinuclidines / metabolism*
  • Rats
  • Receptors, Nicotinic / metabolism*
  • alpha7 Nicotinic Acetylcholine Receptor

Substances

  • Chrna7 protein, human
  • Chrna7 protein, rat
  • Ligands
  • Quinuclidines
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor