Discovery, cocrystallization and biological evaluation of novel piperidine derivatives as high affinity Ls-AChBP ligands possessing α7 nAChR activities

Eur J Med Chem. 2018 Dec 5;160:37-48. doi: 10.1016/j.ejmech.2018.09.073. Epub 2018 Oct 3.


A series of novel pyridine-substituted piperidine derivatives were discovered as low nanomolar Ls-AChBP ligands with α7 nAChR partial agonism or antagonism activities. A high-resolution antagonist-bound Ls-AChBP complex was successfully resolved with a classic Loop C opening phenomenon and unique sulfur-π interactions which deviated from our previous docking mode to a large extent. With the knowledge of the co-complex, 27 novel piperidine derivatives were designed and synthesized. The structure-activity relationships (SARs) of the aromatic and pyridine regions were well established and binding modes were illustrated with the help of molecular docking which indicated that interactions with Trp 143 and the "water bridge" are essential for the high binding affinities. Halogen bonding as well as the space around 5'- or 6'- position of the pyridine ring was also proposed to influence the binding conformation of the compounds. Notably, two enantiomers of compound 2 showed opposite functions toward α7 nAChR and compound (S)-2 showed sub-nanomolar affinity (Ki = 0.86 nM) on Ls-AChBP and partial agonism (pEC50 = 4.69 ± 0.11,Emax = 36.1%) on α7 nAChR with reasonable pharmacokinetics (PK) properties and fine ability of blood-brain-barrier (BBB) penetration. This study provided promising hits to develop candidates targeting nAChR-related CNS diseases.

Keywords: Cocrystallization; Ls-AChBP; Molecular docking; Piperidine derivatives; α7 nAChR.

MeSH terms

  • Animals
  • Carrier Proteins / antagonists & inhibitors*
  • Carrier Proteins / metabolism
  • Crystallography, X-Ray
  • Dose-Response Relationship, Drug
  • Drug Discovery*
  • Humans
  • Ligands
  • Lymnaea
  • Models, Molecular
  • Molecular Structure
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology*
  • Piperidines / chemical synthesis
  • Piperidines / chemistry
  • Piperidines / pharmacology*
  • Structure-Activity Relationship
  • alpha7 Nicotinic Acetylcholine Receptor / agonists*
  • alpha7 Nicotinic Acetylcholine Receptor / metabolism


  • AChBP protein, Lymnaea
  • Carrier Proteins
  • Ligands
  • Nicotinic Agonists
  • Piperidines
  • alpha7 Nicotinic Acetylcholine Receptor
  • piperidine