title: Synthesis of new melatoninergic hexahydroindenopyridines.
abstract: Hexahydroindenopyridine (HHIP) is an interesting heterocyclic framework that contains an indene core similar to ramelteon. This type of tricyclic piperidines aroused our interest as potential melatoninergic ligands. Melatonin receptor ligands have applications in insomnia and depression. We report herein an efficient two-step method to prepare new HHIP by the reaction of an enamine with 3-bromopropylamine hydrobromide. Some synthesized compounds showed moderate affinity for melatonin receptors in the nanomolar or low micromolar range. Furthermore, the methylenedioxy HHIPs 2d (N-phenylacetamide) and 2f (N,N-diethylacetamide), exhibited high selectivity at MT1 or MT2 receptors, respectively, when compared with melatonin. It seems that the methylenedioxy group on the indene ring system and the N-acetamide substituent are important structural features to bind selectively MT1 or MT2 subtypes.
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain. Electronic address: laura.moreno@uv.es.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Berenguer
authors.affiliation: Departamento de Química Orgánica, Facultad de Ciencias, Universidad de Málaga, 29071 Málaga, Spain.
authors.forename: Amelia
authors.initials: A
authors.lastname: Diaz
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Marín
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Párraga
authors.affiliation: Départament des Sciences Expérimentales, Institut de Recherches Servier, 92150 Suresnes, France.
authors.forename: Daniel-Henri
authors.initials: DH
authors.lastname: Caignard
authors.affiliation: UMR CNRS 8076, LERMIT, Université Paris-Sud, Laboratoire de Pharmacognosie, UFR de Pharmacie, Châtenay-Malabry F-92296, France.
authors.forename: Bruno
authors.initials: B
authors.lastname: Figadère
authors.affiliation: Centro de Ecología Química Agrícola-Instituto Agroforestal Mediterraneo, UPV, Campus de Vera, Edificio 6C, 46022 Valencia, Spain. Electronic address: ncabedo@ceqa.upv.es.
authors.forename: Nuria
authors.initials: N
authors.lastname: Cabedo
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, 46100 Burjassot, Valencia, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Cortes
mesh_terms: D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006576:Heterocyclic Compounds, 4 or More Rings / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors*; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D006576:Heterocyclic Compounds, 4 or More Rings; D008024:Ligands; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2
keywords: Hexahydroindenopyridines; Melatonin; Receptor binding; Synthesis