title: Synthesis and pharmacological evaluation of a series of the agomelatine analogues as melatonin MT1 /MT2 agonist and 5-HT2C antagonist.
abstract: Agomelatine is a naphthalenic analogue of melatonin that is in clinical use for the treatment of major depressive disorders. Interestingly, while agomelatine exhibits potent affinity for melatonin receptors, it binds with only moderate affinity to the serotonin 5-HT2C receptor. Optimization of agomelatine toward this target could further potentiate its clinical efficacy. To explore this hypothesis and to access derivatives in which a key point of agomelatine metabolism is blocked, a series of naphthalenic derivatives was designed and synthesized as novel analogues of agomelatine. Most of the prepared compounds exhibited good binding affinity at the melatonin MT1 and MT2 receptor subtypes. Two compounds, an acetamide and an acrylamide derivative, exhibited good binding affinities at both the human melatonin (MT) receptors and the serotonin 5-HT2C receptor subtype, with pKi values of 7.96 and 7.95 against MT1, 7.86 and 8.68 against MT2, and 6.64 and 6.44 against 5-HT2C, respectively.
authors.affiliation: Université Lille Nord de France; UDSL, EA GRIIOT, UFR Pharmacie, Université du Droit et de la Santé de Lille, 59000 Lille (France). m.ettaoussi@yahoo.fr.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ettaoussi
authors.forename: Ahmed
authors.initials: A
authors.lastname: Sabaouni
authors.forename: Basile
authors.initials: B
authors.lastname: Pérès
authors.forename: Elodie
authors.initials: E
authors.lastname: Landagaray
authors.forename: Olivier
authors.initials: O
authors.lastname: Nosjean
authors.forename: Jean A
authors.initials: JA
authors.lastname: Boutin
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.forename: Philippe
authors.initials: P
authors.lastname: Delagrange
authors.forename: Pascal
authors.initials: P
authors.lastname: Berthelot
authors.forename: Saïd
authors.initials: S
authors.lastname: Yous
mesh_terms: D000081:Acetamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D006993:Hypnotics and Sedatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D009281:Naphthalenes / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D044122:Receptor, Melatonin, MT1 / Q000819:agonists*; D058830:Serotonin 5-HT2 Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000081:Acetamides; D006993:Hypnotics and Sedatives; D009281:Naphthalenes; D044122:Receptor, Melatonin, MT1; D058830:Serotonin 5-HT2 Receptor Antagonists; C084711:agomelatine; C031721:naphthalene
keywords: 5-HT2C receptors; agomelatine; antidepressant agents; melatonin receptors; subtype selectivity