Novel N-aryl nicotinamide derivatives: Taking stock on 3,6-diazabicyclo[3.1.1]heptanes as ligands for neuronal acetylcholine receptors

Eur J Med Chem. 2019 Oct 15:180:51-61. doi: 10.1016/j.ejmech.2019.06.079. Epub 2019 Jul 5.

Abstract

We designed the synthesis of a small library of 3-substituted-3,6-diazabicyclo[3.1.1]heptanes whose affinity on neuronal nicotinic receptors (nAChRs) was evaluated. Among the synthesized compounds, the 5-(3,6-diazabicyclo[3.1.1]heptane-3-yl)-N-(2-fluorophenyl)nicotinamide 43 proved to be the most interesting compound with α4β2Ki value of 10 pM and a very high α7/α4β2 selectivity. Furthermore, compounds 35, 39 and 43 elicited a selective partial agonist activity for α4β2 nAChR subtype. Finally, in this paper we also report the conclusions on the 3,6-diazabicyclo[3.1.1]heptanes as ligands for nAChRs, resulting from our consolidated structure activity relationship (SAR) studies on this template.

Keywords: 3,6-diazabicyclo[3.1.1]heptanes; Molecular docking; Partial agonists; Synthesis; Tobacco addiction; nAChRs; α(4)β(2) selectivity.

MeSH terms

  • Azabicyclo Compounds / chemical synthesis
  • Azabicyclo Compounds / chemistry
  • Azabicyclo Compounds / pharmacology*
  • Cell Line
  • Dose-Response Relationship, Drug
  • Humans
  • Ligands
  • Molecular Docking Simulation
  • Molecular Structure
  • Neurons / drug effects*
  • Neurons / metabolism
  • Niacinamide / chemical synthesis
  • Niacinamide / chemistry
  • Niacinamide / pharmacology*
  • Nicotinic Agonists / chemical synthesis
  • Nicotinic Agonists / chemistry
  • Nicotinic Agonists / pharmacology*
  • Receptors, Nicotinic / metabolism*
  • Structure-Activity Relationship

Substances

  • Azabicyclo Compounds
  • Ligands
  • Nicotinic Agonists
  • Receptors, Nicotinic
  • Niacinamide