Design,synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT1 melatoninergic ligands |
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Authors: | Christophe Mésangeau Basile Pérès Carole Descamps-François Philippe Chavatte Valérie Audinot Sophie Coumailleau Jean A Boutin Philippe Delagrange Caroline Bennejean Pierre Renard Daniel H Caignard Pascal Berthelot Saïd Yous |
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Institution: | 1. Univ Lille Nord de France, F-59000 Lille, France;2. UDSL, EA GRIIOT, UFR Pharmacie, F-59000 Lille, France;3. Département des Sciences Expérimentales, Institut de Recherches Servier, 92150 Suresnes, France;4. Institut de Recherches Servier, 78290 Croissy-sur-Seine, France |
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Abstract: | 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. |
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