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.
Highlights
Melatonin (1, Figure 1) is a tryptophan-derived hormone primarily secreted by the pineal gland according to a circadian rhythm, with peak concentrations at night
The key starting alcohols 11a, 11c–d were prepared from the suitable aldehydes 8a, 8c–d following the previously reported three-step sequence (Wittig reaction, hydrogenation, LiAlH4 ester reduction) [48], whereas the alcohol 11b could be obtained by direct reduction of the aldehyde 8d [48]
The chemical physical data are identical to those reported in literature [48]
Summary
Melatonin (1, Figure 1) is a tryptophan-derived hormone primarily secreted by the pineal gland according to a circadian rhythm, with peak concentrations at night. Experimental evidence highlights the important role played by the activation of MT1 and MT2 receptors in sustaining its antioxidant and neuroprotective actions [11,12,13,14]. In motoneurons melatonin attenuated the production of reactive oxygen species, modulated Ca2+ levels and inhibited proapoptotic signaling [11,12]. In this context, melatonin and synthetic compounds, like 2-iodomelatonin or other non-indole melatonergic ligands, have shown to efficiently produce antioxidant and cytoprotective effects and to block neurodegenerative processes both in vitro and in vivo [15,16]. Different series of dual-acting compounds, constituted by melatonin linked to another known neuroprotective agent, have been reported as novel potential therapeutic agents for the treatment of neurodegenerative disorders
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