New agonists at the G-protein-coupled melatonin receptors: pharmacological evaluation as melatonergic ligands ans as neurogenic agents

Resumen del trabajo presentado a la 35th Edition of the European School of Medicinal Chemistry, celebrada en Urbino (Italia) del 28 de junio al 3 de julio del 2015.Melatonin is an endogenous molecule that is present in a variety of organisms, such as bacteria, unicellular algae, fungi, plants, vertebrates, and mammalians, including humans. In mammals, it is secreted by the pineal gland and released into blood circulation according to a circadian rhythm with higher levels at night. It exerts a plethora of physiological and pharmacological actions, like circadian and seasonal regulation, immune and antioxidant systems, and promotion of endogenous brain neurogenesis. Recently, we have developed a new family of melatonin-based compounds, in which the acetamido group has been bioisosterically replaced with different azoles. These compounds bind to melatonergic receptors (MT1R and MT2R) and are potent neurogenic stimulants. Taking into account these results, we have carried out molecular modelling studies, superimposing a melatonin agonist from this series with the bioactive conformation of melatonin. Thus, in this work we have designed and synthesized new 5-methoxyindole derivatives containing different azoles, which have been assayed as melatonergic ligands in a Xenopus laevis culture.Peer Reviewe