New selective ligands of human cloned melatonin MT1 and MT2 receptors

被引:217
作者
Audinot, V
Mailliet, F
Lahaye-Brasseur, C
Bonnaud, A
Le Gall, A
Amossé, C
Dromaint, S
Rodriguez, M
Nagel, N
Galizzi, JP
Malpaux, B
Guillaumet, G
Lesieur, D
Lefoulon, F
Renard, P
Delagrange, P
Boutin, JA
机构
[1] Inst Rech Servier, Div Pharmacol Mol & Cellulaire, F-78290 Croissy Sur Seine, France
[2] Univ Tours, UMR 6073, INRA, CNRS, F-37380 Nouzilly, France
[3] Univ Orleans, CNRS, Inst Chim Organ Analyt, UMR 6005, F-45067 Orleans, France
[4] Univ Lille 2, Inst Chim Pharmaceut, F-59006 Lille, France
[5] Technol Servier, F-45007 Orleans, France
[6] Inst Rech Int Servier, F-92415 Courbevoie, France
关键词
melatonin; melatonin receptors; selective agonists; selective antagonists;
D O I
10.1007/s00210-003-0751-2
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 hMT(1) and hMT(2) receptors stably expressed in HEK-293 or CHO cells is presented using a 2-[I-125]-iodo-melatonin binding assay and a [S-35]-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 hMT(1) and hMT(2) ligands are described. The [S-35]-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.
引用
收藏
页码:553 / 561
页数:9
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