Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT1 melatoninergic ligands

被引：21
作者：
Mesangeau, Christophe [1 ,2 ]
Peres, Basile [1 ,2 ]
Descamps-Francois, Carole [1 ,2 ]
Chavatte, Philippe [1 ,2 ]
Audinot, Valerie [4 ]
Coumailleau, Sophie [4 ]
Boutin, Jean A. [4 ]
Delagrange, Philippe [3 ]
Bennejean, Caroline [4 ]
Renard, Pierre [3 ]
Caignard, Daniel H. [3 ]
Berthelot, Pascal [1 ,2 ]
Yous, Said [1 ,2 ]
机构：
[1] Univ Lille Nord France, F-59000 Lille, France
[2] UFR Pharm, UDSL, EA GRIIOT, F-59000 Lille, France
[3] Inst Rech Servier, Dept Sci Expt, F-92150 Suresnes, France
[4] Inst Rech Servier, F-78290 Croissy Sur Seine, France
来源：
BIOORGANIC & MEDICINAL CHEMISTRY | 2010年 / 18卷 / 10期
关键词：
Melatonin; MT1; Antagonist; Selective ligands; HIGH-AFFINITY; TETRAHYDRONAPHTHALENIC DERIVATIVES; RECEPTOR ANTAGONISTS; SUBTYPE; AGONIST; RETINA; DIMERS;
D O I：
10.1016/j.bmc.2010.04.008
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
Novel heterodimer analogues of melatonin were synthesized, when agomelatine (1) and various aryl units are linked via a linear alkyl chain through the methoxy group. The compounds were tested for their actions at melatonin receptors. Several of these ligands are MT1-selective with nanomolar or subnanomolar affinity. In addition, while most of the derivatives behave as partial agonists on one or both receptor subtypes, N-[2-(7-{4-[6-(1-methoxycarbonylethyl)naphthalen-2-yloxy]butoxy}naphthalen-1-yl)ethyl]acetamide (36), a subnanomolar MT1 ligand with an 11-fold preference over MT2 receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT1 receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers. (C) 2010 Elsevier Ltd. All rights reserved.
引用
收藏
页码：3426 / 3436
页数：11
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