Chronobiotic activity of N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]-propanamide. Synthesis and melatonergic pharmacology of fluoren-9-ylethyl amides

Bioorg Med Chem. 2004 Sep 1;12(17):4601-11. doi: 10.1016/j.bmc.2004.07.002.

Abstract

A series of fluoren-9-yl ethyl amides (2) were synthesized and evaluated for human melatonin MT(1) and MT(2) receptor binding. N-[2-(2,7-dimethoxyfluoren-9-yl)ethyl]propanamide (2b) was selected and evaluated in functional assays measuring intrinsic activity at the human MT(1) and MT(2) receptors and demonstrated full agonism at both receptors. The chronobiotic properties of 2b were demonstrated in both acute and chronic rat models where 2b produced an acute phase advance of 32 min at 1mg/kg and chronically entrained free-running rats with a mean effective dose of 0.23 mg/kg. Compound 2b is significantly less efficacious than melatonin in constricting human coronary artery.

MeSH terms

  • Amides / chemical synthesis
  • Amides / pharmacology
  • Animals
  • Binding Sites
  • Chronobiology Phenomena / physiology*
  • Dose-Response Relationship, Drug
  • Fluorenes / chemistry*
  • Humans
  • Melatonin / metabolism*
  • Mice
  • NIH 3T3 Cells
  • Radioligand Assay
  • Rats
  • Receptors, Melatonin / metabolism
  • Structure-Activity Relationship

Substances

  • Amides
  • Fluorenes
  • Receptors, Melatonin
  • Melatonin