Synthesis and Characterization of New Bivalent Agents as Melatonin- and Histamine H3-Ligands

International Journal of Molecular Sciences

Daniele Pala³  Laura Scalvini³  Alessio Lodola³  Marco Mor³  Lisa Flammini³  Elisabetta Barocelli³  Valeria Lucini¹  Francesco Scaglione¹  Silvia Bartolucci²  Annalida Bedini²  Silvia Rivara³ 

[1] Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, Via Vanvitelli 32, I-20129 Milano, Italy; E-Mails:;Dipartimento di Scienze Biomolecolari, Università degli Studi di Urbino “Carlo Bo”, Piazza Rinascimento 6, I-61029 Urbino, Italy; E-Mails:;Dipartimento di Farmacia, Università degli Studi di Parma, Parco Area delle Scienze 27/A, I-43124 Parma, Italy; E-Mails:

关键词: melatonin receptor;    MT₁;    MT₂;    H₃ antagonists;    bivalent ligands;   

DOI  :  10.3390/ijms150916114

来源: mdpi

【 摘 要 】

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.

【 授权许可】

CC BY   
© 2014 by the authors; licensee MDPI, Basel, Switzerland.