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.
Christophe Mésangeau  1 ,  Basile Pérès ,  Carole Descamps-François ,  Philippe Chavatte ,  Valérie Audinot ,  Sophie Coumailleau ,  Jean A Boutin ,  Philippe Delagrange ,  Caroline Bennejean ,  Pierre Renard ,  Daniel H Caignard ,  Pascal Berthelot ,  Saïd Yous
Affiliations
  • 1. Univ Lille Nord de France, F-59000 Lille, France.
PMID: 20444610 DOI: 10.1016/j.bmc.2010.04.008
Abstract

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.