Epiboxidine and novel-related analogues: a convenient synthetic approach and estimation of their affinity at neuronal nicotinic acetylcholine receptor subtypes

Bioorg Med Chem Lett. 2008 Aug 15;18(16):4651-4. doi: 10.1016/j.bmcl.2008.07.016. Epub 2008 Jul 10.

Abstract

Racemic exo-epiboxidine 3, endo-epiboxidine 6, and the two unsaturated epiboxidine-related derivatives 7 and 8 were efficiently prepared taking advantage of a palladium-catalyzed Stille coupling as the key step in the reaction sequence. The target compounds were assayed for their binding affinity at neuronal alpha4beta2 and alpha7 nicotinic acetylcholine receptors. Epiboxidine 3 behaved as a high affinity alpha4beta2 ligand (K(i)=0.4 nM) and, interestingly, evidenced a relevant affinity also for the alpha7 subtype (K(i)=6 nM). Derivative 7, the closest analogue of 3 in this group, bound with lower affinity at both receptor subtypes (K(i)=50 nM for alpha4beta2 and K(i)=1.6 microM for alpha7) evidenced a gain in the alpha4beta2 versus alpha7 selectivity when compared with the model compound.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Binding, Competitive
  • Catalysis
  • Cerebral Cortex / drug effects
  • Chemistry, Pharmaceutical
  • Drug Design
  • Isoxazoles / chemical synthesis*
  • Isoxazoles / chemistry
  • Isoxazoles / pharmacology*
  • Kinetics
  • Ligands
  • Models, Chemical
  • Neurons / metabolism
  • Rats
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / drug effects*
  • Structure-Activity Relationship
  • Temperature

Substances

  • Isoxazoles
  • Ligands
  • Receptors, Nicotinic
  • epiboxidine