title: Efficient synthesis of hexahydroindenopyridines and their potential as melatoninergic ligands.
abstract: Hexahydroindenopyridine (HHIP) is an interesting tricyclic piperidine nucleus that is structurally related to melatonin, a serotonin-derived neurohormone. Melatonin receptor ligands have applications in several cellular, neuroendocrine and neurophysiological disorders, including depression and/or insomnia. We report herein an efficient two-step method to prepare new HHIP via enamine C-alkylation-cyclization. The influence of substituents on the benzene ring and the nitrogen atom on melatoninergic receptors has been studied. Among the 25 synthesized HHIPs, some of them containing methylenedioxy (series 2) and 8-chloro-7-methoxy substituents (series 4) on the benzene ring revealed affinity for the MT1 and/or the MT2 receptors within the nanomolar range or low micromolar. Similar activities were also encountered for those presenting urea (4g), N-aryl (2e) and N-alkyl (2f) acetamide functions. Therefore, new synthesized compounds with a HHIP nucleus have emerged as new promising leads towards the discovery of melatoninergic ligands which could provide new therapeutic agents.
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, Burjassot, 46100 Valencia, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Párraga
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, Burjassot, 46100 Valencia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Moreno
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, Burjassot, 46100 Valencia, Spain.
authors.forename: Noureddine
authors.initials: N
authors.lastname: El Aouad
authors.affiliation: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, Burjassot, 46100 Valencia, Spain.
authors.forename: Abraham
authors.initials: A
authors.lastname: Galán
authors.affiliation: Departamento de Farmacología, Facultad de Medicina, Universidad de Valencia, 46010 Valencia, Spain; Institute of Health Research-INCLIVA, University Clinic Hospital of Valencia, Valencia, Spain.
authors.forename: María Jesús
authors.initials: MJ
authors.lastname: Sanz
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: Departamento de Farmacología, Laboratorio de Farmacoquímica, Facultad de Farmacia, Universidad de Valencia, Burjassot, 46100 Valencia, Spain; 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, Burjassot, 46100 Valencia, Spain.
authors.forename: Diego
authors.initials: D
authors.lastname: Cortes
mesh_terms: D001665:Binding Sites; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D057809:HEK293 Cells; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism*; D044122:Receptor, Melatonin, MT1 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D044123:Receptor, Melatonin, MT2 / Q000819:agonists / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship
chemical_list: D008024:Ligands; D011725:Pyridines; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2
keywords: Hexahydroindenopyridines; MT(1) and MT(2) receptor binding; Melatonin; Synthesis