title: Design, synthesis and pharmacological evaluation of novel naphthalenic derivatives as selective MT(1) melatoninergic ligands.
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 MT(1)-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 MT(1) ligand with an 11-fold preference over MT(2) receptors, is a full antagonist on both receptors. Our results also confirm that the selectivity seen for the MT(1) receptor arises predominantly from steric factors and is not a consequence of the bridging of melatonin receptor dimers.
authors.affiliation: Univ Lille Nord de France, F-59000 Lille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Mésangeau
authors.forename: Basile
authors.initials: B
authors.lastname: Pérès
authors.forename: Carole
authors.initials: C
authors.lastname: Descamps-François
authors.forename: Philippe
authors.initials: P
authors.lastname: Chavatte
authors.forename: Valérie
authors.initials: V
authors.lastname: Audinot
authors.forename: Sophie
authors.initials: S
authors.lastname: Coumailleau
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Caroline
authors.initials: C
authors.lastname: Bennejean
authors.forename: Pierre
authors.initials: P
authors.lastname: Renard
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Caignard
authors.forename: Pascal
authors.initials: P
authors.lastname: Berthelot
authors.forename: Saïd
authors.initials: S
authors.lastname: Yous
mesh_terms: D000081:Acetamides / Q000494:pharmacology*; D000818:Animals; D001665:Binding Sites; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D008550:Melatonin / Q000819:agonists; D011485:Protein Binding; D021281:Quantitative Structure-Activity Relationship; D044122:Receptor, Melatonin, MT1; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors*; D009281:Naphthalenes
chemical_list: D000081:Acetamides; D008550:Melatonin; D044122:Receptor, Melatonin, MT1; D044094:Receptors, Melatonin; C084711:agomelatine; D009281:Naphthalenes