New selective ligands of human cloned melatonin MT1 and MT2 receptors.
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.
Audinot
Valérie
V
Division de Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125, Chemin de Ronde, 78290 Croissy-sur-Seine, France.
Mailliet
François
F
Lahaye-Brasseur
Chantal
C
Bonnaud
Anne
A
Le Gall
Aude
A
Amossé
Christophe
C
Dromaint
Sandra
S
Rodriguez
Marianne
M
Nagel
Nadine
N
Galizzi
Jean-Pierre
JP
Malpaux
Benoît
B
Guillaumet
Gérald
G
Lesieur
Daniel
D
Lefoulon
François
F
Renard
Pierre
P
Delagrange
Philippe
P
Boutin
Jean A
JA
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*
D008024:Ligands; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D008550:Melatonin