title: Novel N-Acetyl Bioisosteres of Melatonin: Melatonergic Receptor Pharmacology, Physicochemical Studies, and Phenotypic Assessment of Their Neurogenic Potential.
abstract: 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.
authors.affiliation: †Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Mario
authors.initials: M
authors.lastname: de la Fuente Revenga
authors.affiliation: †Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Nerea
authors.initials: N
authors.lastname: Fernández-Sáez
authors.affiliation: †Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Clara
authors.initials: C
authors.lastname: Herrera-Arozamena
authors.affiliation: ‡Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (IIB-CSIC), C/Arturo Duperier 4, 28029 Madrid, Spain.|§Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031 Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Morales-García
authors.affiliation: ‡Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (IIB-CSIC), C/Arturo Duperier 4, 28029 Madrid, Spain.|§Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031 Madrid, Spain.
authors.forename: Sandra
authors.initials: S
authors.lastname: Alonso-Gil
authors.affiliation: ‡Instituto de Investigaciones Biomédicas "Alberto Sols", Consejo Superior de Investigaciones Científicas (IIB-CSIC), C/Arturo Duperier 4, 28029 Madrid, Spain.|§Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031 Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Pérez-Castillo
authors.affiliation: ∥Institut de Recherches Servier, 125 Chemin de Ronde, 78290 Croissy sur Seine, France.
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.affiliation: ⊥Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, 43124 Parma, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: †Instituto de Química Médica, Consejo Superior de Investigaciones Científicas (IQM-CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
mesh_terms: D000818:Animals; D016466:CHO Cells; D002478:Cells, Cultured; D003412:Cricetulus; D006801:Humans; D008297:Male; D008550:Melatonin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D008958:Models, Molecular; D058953:Neural Stem Cells / Q000166:cytology / Q000187:drug effects; D055495:Neurogenesis / Q000187:drug effects*; D010069:Oxadiazoles / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D044094:Receptors, Melatonin / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013830:Thiadiazoles / Q000737:chemistry / Q000494:pharmacology
chemical_list: D010069:Oxadiazoles; D044094:Receptors, Melatonin; D013830:Thiadiazoles; C058949:1,3,4-thiadiazole; C583463:1,3,4-oxadiazole; D008550:Melatonin