2. Academic Validation
  3. New MT₂ Melatonin Receptor-Selective Ligands: Agonists and Partial Agonists

New MT₂ Melatonin Receptor-Selective Ligands: Agonists and Partial Agonists

  • Int J Mol Sci. 2017 Jun 23;18(7):1347. doi: 10.3390/ijms18071347.
Jean A Boutin 1 2,  Anne Bonnaud 3,  Chantal Brasseur 4,  Olivier Bruno 5,  Nolwenn Lepretre 6,  Peter Oosting 7,  Sophie Coumailleau 8,  Philippe Delagrange 9,  Olivier Nosjean 10 11,  Céline Legros 12
Affiliations

Affiliations

  • 1 Pôle d'Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
  • 2 Pôle d'Expertise Recherches & BioPharmacie, Institut de Recherches Internationales SERVIER, 92150 Suresnes, France. [email protected].
  • 3 Pôle d'Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
  • 4 Pôle d'Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
  • 5 Pôle d'Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
  • 6 DIVERCHIM S.A., 95700 Roissy-en-France, France. [email protected].
  • 7 DIVERCHIM S.A., 95700 Roissy-en-France, France. [email protected].
  • 8 Pôle d'Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
  • 9 Pôle d'Innovations Thérapeutiques en Neurosciences, Institut de Recherches, SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
  • 10 Pôle d'Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
  • 11 Pôle d'Expertise Recherches & BioPharmacie, Institut de Recherches Internationales SERVIER, 92150 Suresnes, France. [email protected].
  • 12 Pôle d'Expertise Biotechnologie, Chimie, Biologie, Institut de Recherches SERVIER, 78290 Croissy-sur-Seine, France. [email protected].
PMID: 28644418 DOI: 10.3390/ijms18071347
Abstract

The search for Melatonin Receptor agonists and antagonists specific towards one of the receptor subtypes will extend our understanding of the role of this system in relaying circadian information to the body. A series of compounds derived from a hit compound discovered in a screening process led to powerful agonists specific for one of the isoform of the Melatonin Receptor namely, MT₂. The compounds are based on a poorly explored skeleton in the molecular pharmacology of melatonin. By changing the steric hindrance of one substituent (i.e., from a hydrogen atom to a tributylstannyl group), we identified a possible partial agonist that could lead to antagonist analogues. The functionalities of these compounds were measured with a series of assays, including the binding of GTPγS, the inhibition of the cyclic AMP production, the β-arrestin recruitment, and the cell shape changes as determined by cellular dielectric spectroscopy (CellKey®). The variations between the compounds are discussed.

Keywords

agonist; functional assays; melatonin receptors; molecular pharmacology; partial agonist.

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