Discovery and optimization of substituted piperidines as potent, selective, CNS-penetrant alpha4beta2 nicotinic acetylcholine receptor potentiators

Bioorg Med Chem Lett. 2008 Oct 1;18(19):5209-12. doi: 10.1016/j.bmcl.2008.08.080. Epub 2008 Aug 28.


The discovery of a series of small molecule alpha4beta2 nAChR potentiators is reported. The structure-activity relationship leads to potent compounds selective against nAChRs including alpha3beta2 and alpha3beta4 and optimized for CNS penetrance. Compounds increased currents through recombinant alpha4beta2 nAChRs, yet did not compete for binding with the orthosteric ligand cytisine. High potency and efficacy on the rat channel combined with good PK properties will allow testing of the alpha4beta2 potentiator mechanism in animal models of disease.

MeSH terms

  • Animals
  • Central Nervous System / drug effects*
  • Combinatorial Chemistry Techniques
  • Disease Models, Animal
  • Humans
  • Molecular Structure
  • Nicotinic Agonists / pharmacology*
  • Piperidines / chemical synthesis*
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Rats
  • Receptors, Nicotinic / chemistry
  • Receptors, Nicotinic / drug effects*
  • Structure-Activity Relationship


  • Nicotinic Agonists
  • Piperidines
  • Receptors, Nicotinic
  • nicotinic receptor alpha4beta2