title: Synthesis and characterization of new bivalent agents as melatonin- and histamine H3-ligands.
abstract: Melatonin is an endogenous molecule involved in many pathophysiological processes. In addition to the control of circadian rhythms, its antioxidant and neuroprotective properties have been widely described. Thus far, different bivalent compounds composed by a melatonin molecule linked to another neuroprotective agent were synthesized and tested for their ability to block neurodegenerative processes in vitro and in vivo. To identify a novel class of potential neuroprotective compounds, we prepared a series of bivalent ligands, in which a prototypic melatonergic ligand is connected to an imidazole-based H3 receptor antagonist through a flexible linker. Four imidazolyl-alkyloxy-anilinoethylamide derivatives, characterized by linkers of different length, were synthesized and their binding affinity for human MT1, MT2 and H3 receptor subtypes was evaluated. Among the tested compounds, 14c and 14d, bearing a pentyl and a hexyl linker, respectively, were able to bind to all receptor subtypes at micromolar concentrations and represent the first bivalent melatonergic/histaminergic ligands reported so far. These preliminary results, based on binding affinity evaluation, pave the way for the future development of new dual-acting compounds targeting both melatonin and histamine receptors, which could represent promising therapeutic agents for the treatment of neurodegenerative pathologies.
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. daniele.pala@nemo.unipr.it.
authors.forename: Daniele
authors.initials: D
authors.lastname: Pala
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. laura.scalvini@studenti.unipr.it.
authors.forename: Laura
authors.initials: L
authors.lastname: Scalvini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. alessio.lodola@unipr.it.
authors.forename: Alessio
authors.initials: A
authors.lastname: Lodola
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. marco.mor@unipr.it.
authors.forename: Marco
authors.initials: M
authors.lastname: Mor
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. lisa.flammini@unipr.it.
authors.forename: Lisa
authors.initials: L
authors.lastname: Flammini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. elisabetta.barocelli@unipr.it.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Barocelli
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, I-20129 Milano, Italy. valeria.lucini@unimi.it.
authors.forename: Valeria
authors.initials: V
authors.lastname: Lucini
authors.affiliation: Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, I-20129 Milano, Italy. francesco.scaglione@unimi.it.
authors.forename: Francesco
authors.initials: F
authors.lastname: Scaglione
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", Piazza Rinascimento 6, I-61029 Urbino, Italy. silvia.bartolucci@uniurb.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Bartolucci
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", Piazza Rinascimento 6, I-61029 Urbino, Italy. annalida.bedini@uniurb.it.
authors.forename: Annalida
authors.initials: A
authors.lastname: Bedini
authors.affiliation: Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy. silvia.rivara@unipr.it.
authors.forename: Silvia
authors.initials: S
authors.lastname: Rivara
authors.affiliation: Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino "Carlo Bo", Piazza Rinascimento 6, I-61029 Urbino, Italy. gilberto.spadoni@uniurb.it.
authors.forename: Gilberto
authors.initials: G
authors.lastname: Spadoni
mesh_terms: D001665:Binding Sites; D006633:Histamine Antagonists / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry; D008024:Ligands; D062105:Molecular Docking Simulation; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D044122:Receptor, Melatonin, MT1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D044123:Receptor, Melatonin, MT2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D018100:Receptors, Histamine H3 / Q000737:chemistry* / Q000378:metabolism
chemical_list: D006633:Histamine Antagonists; D007093:Imidazoles; D008024:Ligands; D010880:Piperidines; D044122:Receptor, Melatonin, MT1; D044123:Receptor, Melatonin, MT2; D018100:Receptors, Histamine H3; C029899:imidazole; C052075:thioperamide