title: New selective ligands of human cloned melatonin MT1 and MT2 receptors.
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]-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.
authors.affiliation: Division de Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy-sur-Seine, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Audinot
authors.forename: François
authors.initials: F
authors.lastname: Mailliet
authors.forename: Chantal
authors.initials: C
authors.lastname: Lahaye-Brasseur
authors.forename: Anne
authors.initials: A
authors.lastname: Bonnaud
authors.forename: Aude
authors.initials: A
authors.lastname: Le Gall
authors.forename: Christophe
authors.initials: C
authors.lastname: Amossé
authors.forename: Sandra
authors.initials: S
authors.lastname: Dromaint
authors.forename: Marianne
authors.initials: M
authors.lastname: Rodriguez
authors.forename: Nadine
authors.initials: N
authors.lastname: Nagel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Galizzi
authors.forename: Benoît
authors.initials: B
authors.lastname: Malpaux
authors.forename: Gérald
authors.initials: G
authors.lastname: Guillaumet
authors.forename: Daniel
authors.initials: D
authors.lastname: Lesieur
authors.forename: François
authors.initials: F
authors.lastname: Lefoulon
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D003001:Cloning, Molecular / Q000379:methods*; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008024:Ligands; D008550:Melatonin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding / Q000502:physiology; D044122:Receptor, Melatonin, MT1 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: D008024:Ligands; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D008550:Melatonin