Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential

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Herein we present a new family of melatonin-based compounds, in which the acetamido group of melatonin has been bioisosterically replaced by a series of reversed amides and azoles, such as oxazole, 1,2,4-oxadiazole, and 1,3,4-oxadiazole, as well as other related five-membered heterocycles, namely, 1,3,4-oxadiazol(thio)ones, 1,3,4-triazol(thio)ones, and an 1,3,4-thiadiazole. New compounds were fully characterized at melatonin receptors (MT1R and MT2R), and results were rationalized by superimposition studies of their structures to the bioactive conformation of melatonin. We also found that several of these melatonin-based compounds promoted differentiation of rat neural stem cells to a neuronal phenotype in vitro, in some cases to a higher extent than melatonin. This unique profile constitutes the starting point for further pharmacological studies to assess the mechanistic pathways and the relevance of neurogenesis induced by melatonin-related structures.
We gratefully acknowledge the financial support of the Spanish Ministry of Economy and Competitiveness (MINECO, Grants SAF2012-31035, SAF2010-16365, and SAF2014-52940-R), Fundación de Investigación Médica Mutua Madrileña Automovilística (Grant AP103952012), and Consejo Superior de Investigaciones Científicas (CSIC, Grant PIE-201280E074). The Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED) is funded by the Instituto de Salud Carlos III. M.d.l.F.R. thanks CSIC for a JAE-Predoctoral Contract, and J.A.M.-G. thanks CIBERNED for a postdoctoral fellowship . We also acknowledge Dr. Paula Morales for the binding assays on cannabinoid receptors and the National Institute on Mental Health-Psychoactive Drug Screening Program (NIMH-PDSP, Contract HHSN-271-2013-00017-C, Dr. Bryan Roth) for binding experiments on serotonin receptors and transporter.