Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT(1) melatoninergic ligands

Bioorg Med Chem. 2010 May 15;18(10):3426-36. doi: 10.1016/j.bmc.2010.04.008. Epub 2010 Apr 7.


Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these ligands are MT(1)-selective with nanomolar or subnanomolar affinity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes, N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide (36), a subnanomolar MT(1) ligand with an 11-fold preference over MT(2) receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT(1) receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / pharmacology*
  • Animals
  • Binding Sites
  • Binding, Competitive
  • CHO Cells
  • Cell Line
  • Cricetinae
  • Cricetulus
  • Dose-Response Relationship, Drug
  • Drug Design
  • Melatonin / agonists
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Receptor, Melatonin, MT1
  • Receptors, Melatonin / agonists
  • Receptors, Melatonin / antagonists & inhibitors*


  • Acetamides
  • Receptor, Melatonin, MT1
  • Receptors, Melatonin
  • agomelatine
  • Melatonin