Efficient synthesis of hexahydroindenopyridines and their potential as melatoninergic ligands

Eur J Med Chem. 2014 Oct 30;86:700-9. doi: 10.1016/j.ejmech.2014.09.038. Epub 2014 Sep 16.


Hexahydroindenopyridine (HHIP) is an interesting tricyclic piperidine nucleus that is structurally related to melatonin, a serotonin-derived neurohormone. Melatonin receptor ligands have applications in several cellular, neuroendocrine and neurophysiological disorders, including depression and/or insomnia. We report herein an efficient two-step method to prepare new HHIP via enamine C-alkylation-cyclization. The influence of substituents on the benzene ring and the nitrogen atom on melatoninergic receptors has been studied. Among the 25 synthesized HHIPs, some of them containing methylenedioxy (series 2) and 8-chloro-7-methoxy substituents (series 4) on the benzene ring revealed affinity for the MT1 and/or the MT2 receptors within the nanomolar range or low micromolar. Similar activities were also encountered for those presenting urea (4g), N-aryl (2e) and N-alkyl (2f) acetamide functions. Therefore, new synthesized compounds with a HHIP nucleus have emerged as new promising leads towards the discovery of melatoninergic ligands which could provide new therapeutic agents.

Keywords: Hexahydroindenopyridines; MT(1) and MT(2) receptor binding; Melatonin; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cells, Cultured
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Ligands
  • Molecular Structure
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / metabolism*
  • Receptor, Melatonin, MT1 / agonists
  • Receptor, Melatonin, MT1 / chemistry
  • Receptor, Melatonin, MT1 / metabolism*
  • Receptor, Melatonin, MT2 / agonists
  • Receptor, Melatonin, MT2 / chemistry
  • Receptor, Melatonin, MT2 / metabolism*
  • Structure-Activity Relationship


  • Ligands
  • Pyridines
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2