New selective ligands of human cloned melatonin MT1 and MT2 receptors

• DOI: 10.1007/s00210-003-0751-2
• Publication Date: 2005-12-07T18:05:24Z
• Authors: Valérie Audinot; François Mailliet; Chantal Lahaye-Br...; Anne Bonnaud; Aude Le Gall; Christophe Amossé; Sandra Dromaint; Marianne Rodriguez; Nadine Nagel; Jean-Pierre Galizzi; Benoît Malpaux; Gérald Guillaumet; Daniel Lesieur; François Lefoulon; Pierre Renard; Philippe Delagrange; Jean A. Boutin
• Keywords: HEK 293 cells; Inverse agonist; Cricetulus; Luzindole

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]-GTPgammaS 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]-GTPgammaS 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.