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New selective ligands of human cloned melatonin MT1 and MT2 receptors

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Abstract

Melatonin has a key role in the circadian rhythm relay to periphery organs. Melatonin exerts its multiple roles mainly through two seven transmembrane domain, G-coupled receptors, namely MT1 or MT2 receptors. A pharmacological characterization of these human cloned melatonin hMT1 and hMT2 receptors stably expressed in HEK-293 or CHO cells is presented using a 2-[125I]-iodo-melatonin binding assay and a [35S]-GTPγS functional assay. Both reference compounds and new chemically diverse ligands were evaluated. Binding affinities at each receptor were found to be comparable on either HEK-293 or CHO cell membranes. Novel non-selective or selective hMT1 and hMT2 ligands are described. The [35S]-GTPγS functional assay was used to define the functional activity of these compounds which included partial, full agonist and/or antagonist activity. None of the compounds acted as an inverse agonist. We report new types of selective antagonists, such as S 25567 and S 26131 for MT1 and S 24601 for MT2. These studies brought other new molecular tools such as the selective MT1 agonist, S 24268, as well as the non-selective antagonist, S 22153. Finally, we also discovered S 25150, the most potent melatonin receptor agonist, so far reported in the literature.

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Acknowledgement

The authors gratefully acknowledge the secretarial assistance of Mrs. Michelle Deret.

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Authors and Affiliations

  1. Division de Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125, Chemin de Ronde, 78290, Croissy-sur-Seine, France

    Valérie Audinot, Chantal Lahaye-Brasseur, Anne Bonnaud, Aude Le Gall, Christophe Amossé, Sandra Dromaint, Marianne Rodriguez, Nadine Nagel, Jean-Pierre Galizzi & Jean A. Boutin

  2. Physiologie de la Reproduction et des Comportements, UMR INRA-CNRS-Université de Tours 6073, 37380, Nouzilly, France

    François Mailliet & Benoît Malpaux

  3. Institut de Chimie Organique et Analytique, UMR CNRS 6005, Université d'Orléans, BP 6759, 45067, Orléans Cedex 2, France

    Gérald Guillaumet

  4. Institut de Chimie Pharmaceutique, Université de Lille II, rue du Professeur Laguesse, BP 83, 59006, Lille Cedex, France

    Daniel Lesieur

  5. Technologie Servier, 25, rue Eugène Vignat, 45007, Orléans, France

    François Lefoulon

  6. Institut de Recherches Internationales Servier, 6, place des Pléiades, 92415, Courbevoie Cedex, France

    Pierre Renard & Philippe Delagrange

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  1. Valérie Audinot
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  2. François Mailliet
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  3. Chantal Lahaye-Brasseur
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  12. Gérald Guillaumet
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  13. Daniel Lesieur
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  14. François Lefoulon
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  15. Pierre Renard
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  16. Philippe Delagrange
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  17. Jean A. Boutin
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Correspondence to Jean A. Boutin.

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Audinot, V., Mailliet, F., Lahaye-Brasseur, C. et al. New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmiedeberg's Arch Pharmacol 367, 553–561 (2003). https://doi.org/10.1007/s00210-003-0751-2

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