2. Academic Validation
  3. New melatonin (MT1/MT2) ligands: design and synthesis of (8,9-dihydro-7H-furo[3,2-f]chromen-1-yl) derivatives

New melatonin (MT1/MT2) ligands: design and synthesis of (8,9-dihydro-7H-furo[3,2-f]chromen-1-yl) derivatives

  • Bioorg Med Chem. 2014 Feb 1;22(3):986-96. doi: 10.1016/j.bmc.2013.12.054.
Elodie Landagaray 1,  Mohamed Ettaoussi 2,  Véronique Leclerc 1,  Balla Traoré 1,  Valérie Perez 3,  Olivier Nosjean 3,  Jean A Boutin 3,  Daniel-Henri Caignard 4,  Philippe Delagrange 5,  Pascal Berthelot 1,  Saïd Yous 1
Affiliations

Affiliations

  • 1 Univ. Lille Nord de France, F-59000 Lille, France; UDSL, EA GRIIOT, UFR Pharmacie, F-59000 Lille, France.
  • 2 Univ. Lille Nord de France, F-59000 Lille, France; UDSL, EA GRIIOT, UFR Pharmacie, F-59000 Lille, France. Electronic address: m.ettaoussi@yahoo.fr.
  • 3 Biotechnologies, Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 78290 Croissy-sur-Seine, France.
  • 4 Unité de Recherche Chimie Neurosciences, Institut de Recherches Servier, 78290 Croissy-sur-Seine, France.
  • 5 Unité de Recherches et Découvertes en Neurosciences, Institut de Recherches Servier, 78290 Croissy-sur-Seine, France.
PMID: 24417958 DOI: 10.1016/j.bmc.2013.12.054
Abstract

Herein we describe the synthesis of novel tricyclic analogues issued from the rigidification of the methoxy group of the benzofuranic analogue of melatonin as MT1 and MT2 ligands. Most of the synthesized compounds displayed high binding affinities at MT1 and MT2 receptors subtypes. Compound 6b (MT1, Ki=0.07nM; MT2, Ki=0.08nM) exhibited with the vinyl 6c and allyl 6d the most interesting derivatives of this series. Functional activity of these compounds showed full agonist activity with EC50 in the nanomolar range. Compounds 6a (EC50=0.8nM and Emax=98%) and 6b (EC50=0.2nM and Emax=121%) exhibited good pharmacological profiles.

Keywords

Benzofuran derivatives; CHO; Chinese Hamster Ovary; HEK; Human Embryonic Kidney; MLT; MT(1); MT(2)-selectivity; Melatonin; [(35)S]-GTPγS; guanosine-5′[γ-(35)S]-triphosphate; melatonin.

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