Synthesis and Pharmacological Evaluation of a series of the Agomelatine Analogues as Melatonin MT1/MT2 Agonist and 5‐HT2C Antagonist |
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| Authors: | Dr Mohamed Ettaoussi Dr Ahmed Sabaouni Dr Basile Pérès Elodie Landagaray Dr Olivier Nosjean Dr Jean A Boutin Dr Daniel‐Henri Caignard Dr Philippe Delagrange Prof Pascal Berthelot Dr Saïd Yous |
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| Affiliation: | 1. Université Lille Nord de France;2. UDSL, EA GRIIOT, UFR Pharmacie, Université du Droit et de la Santé de Lille, 59000 Lille (France);3. Biotechnologies, Pharmacologie Moléculaire et Cellulaire, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy‐sur‐Seine (France);4. Unité de Recherches et Découvertes en Neurosciences, Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy‐sur‐Seine (France) |
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| 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. |
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| Keywords: | 5‐HT2C receptors agomelatine antidepressant agents melatonin receptors subtype selectivity |
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