Synthesis of new melatoninergic hexahydroindenopyridines

Bioorg Med Chem Lett. 2014 Aug 1;24(15):3534-6. doi: 10.1016/j.bmcl.2014.05.053. Epub 2014 Jun 2.

Abstract

Hexahydroindenopyridine (HHIP) is an interesting heterocyclic framework that contains an indene core similar to ramelteon. This type of tricyclic piperidines aroused our interest as potential melatoninergic ligands. Melatonin receptor ligands have applications in insomnia and depression. We report herein an efficient two-step method to prepare new HHIP by the reaction of an enamine with 3-bromopropylamine hydrobromide. Some synthesized compounds showed moderate affinity for melatonin receptors in the nanomolar or low micromolar range. Furthermore, the methylenedioxy HHIPs 2d (N-phenylacetamide) and 2f (N,N-diethylacetamide), exhibited high selectivity at MT1 or MT2 receptors, respectively, when compared with melatonin. It seems that the methylenedioxy group on the indene ring system and the N-acetamide substituent are important structural features to bind selectively MT1 or MT2 subtypes.

Keywords: Hexahydroindenopyridines; Melatonin; Receptor binding; Synthesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Heterocyclic Compounds, 4 or More Rings / chemical synthesis
  • Heterocyclic Compounds, 4 or More Rings / chemistry
  • Heterocyclic Compounds, 4 or More Rings / pharmacology*
  • Humans
  • Ligands
  • Molecular Structure
  • Receptor, Melatonin, MT1 / antagonists & inhibitors*
  • Receptor, Melatonin, MT2 / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Heterocyclic Compounds, 4 or More Rings
  • Ligands
  • Receptor, Melatonin, MT1
  • Receptor, Melatonin, MT2