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Synthesis and Pharmacological Evaluation of a series of the Agomelatine Analogues as Melatonin MT 1 /MT 2 Agonist and 5‐HT 2C Antagonist
Author(s) -
Ettaoussi Mohamed,
Sabaouni Ahmed,
Pérès Basile,
Landagaray Elodie,
Nosjean Olivier,
Boutin Jean A.,
Caignard DanielHenri,
Delagrange Philippe,
Berthelot Pascal,
Yous Saïd
Publication year - 2013
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201300294
Subject(s) - agomelatine , melatonin , melatonin receptor , 5 ht receptor , agonist , receptor , serotonin , chemistry , acetamide , pharmacology , antagonist , medicine , biochemistry , antidepressant , hippocampus , organic chemistry
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‐HT 2C 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 MT 1 and MT 2 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‐HT 2C receptor subtype, with p K i values of 7.96 and 7.95 against MT 1 , 7.86 and 8.68 against MT2, and 6.64 and 6.44 against 5‐HT 2C , respectively.