Synthesis of 2-amido-2,3-dihydro-1H-phenalene derivatives as new conformationally restricted ligands for melatonin receptors

J Med Chem. 1996 Aug 2;39(16):3089-95. doi: 10.1021/jm960219h.


Tetrahydroanthracene, tetrahydrophenanthrene, and tetrahydrophenalene moieties were used to design novel constrained melatoninergic agents. Compounds 1 and 2 were synthesized from the cyclization of the aryl succinic acids 6a,b followed by catalytic reduction, Curtius degradation to the amino derivatives, and acetylation. The phenalene derivatives 3 were prepared by cyclization of the aza lactones of the corresponding alpha-N-acetyl amino acids. The ketone derivatives were reduced directly by catalytic hydrogenation to produce the compounds 3. The different compounds were evaluated in vitro in binding assays using 2-[125I] iodomelatonin and chicken brain membranes. Melatonin and 2-acetamido-8-methoxytetralin were used as the reference compounds. The results showed the superiority of the dihydrophenalene framework 3 over those of tetrahydroanthracene and tetrahydrophenanthrene. 3a had relatively good affinity for melatonin receptors (Ki = 28.7 nM). Introduction of an additional methoxy group gave a derivative (3c) with nanomolar affinity (Ki = 0.7 nM), confirming the existence of a secondary binding site in the receptor which has been described previously. An increase in the affinity was also observed with the propionamido derivative 3e (Ki = 6.0 nM). The potential agonist properties of the compound 3e were evaluated on the dermal melanocytes of Xenopus laevis tadpoles. At the concentration of 2.3 nM (5 x Ki), melatonin gave a melanophore index value of 1. Similarly to melatonin, 3e was shown to be a potent agonist of the melanosome aggregation.

MeSH terms

  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / metabolism
  • Amides / pharmacology
  • Animals
  • Ligands
  • Magnetic Resonance Spectroscopy
  • Melanocytes / drug effects*
  • Melanocytes / physiology
  • Melanophores / drug effects
  • Melatonin / metabolism
  • Molecular Conformation
  • Molecular Structure
  • Polycyclic Compounds / chemical synthesis*
  • Polycyclic Compounds / chemistry
  • Polycyclic Compounds / metabolism
  • Polycyclic Compounds / pharmacology
  • Receptors, Cell Surface / agonists*
  • Receptors, Cell Surface / metabolism*
  • Receptors, Melatonin
  • Structure-Activity Relationship
  • Xenopus laevis


  • Amides
  • Ligands
  • Polycyclic Compounds
  • Receptors, Cell Surface
  • Receptors, Melatonin
  • Melatonin