Synthesis and Chemical Optimization of New Melatonergic Ligands, including Multitarget Compounds

Complex multifactorial pathologies, such as metabolic syndrome, psychiatric or degenerative central nervous system disorders, and cancer, are often caused by deregulation of multiple pathways, and cannot be effectively treated with a single-target modulation. Therefore, the use of multitarget compounds represents a more valid and effective strategy for these pathologies. Both melatonin and endocannabinoid are pleiotropic signaling system involved in all aspects of mammalian physiology and pathology, and for this reason they represents potential targets for the design and development of new therapeutic drugs. In my thesis work, I focused my attention on the synthesis of a different series of melatoninergic ligands, including new multitarget compounds able to also modulate the endocannabinoid system. The single enantiomers of (±)-UCM1014, a potent and selective MT2-receptor agonist, were obtained through an appropriate optical resolution strategy. Pharmacological experiments demonstrated that (R)-UCM1014 is the eutomer, with about 160-fold selectivity for the MT2 receptor and full agonist behaviour. The combination of molecular docking simulations and investigation of the conformational equilibria in solution by molecular dynamics simulations and NMR spectroscopy allowed us to rationalize the stereoselective behavior shown by the two enantiomers. New melatonergic fluorescent probes were synthetized, introducing on the C-4 position of MLT indole a formyl moiety (CHO) and a cyano (CN) group. The 4-CHO-MLT and the 4-CN-MLT gave the desired red-shifted absorption and emission spectra, but a diminished binding affinity for the two receptors was observed. The chemical optimization of UCM765, a MT2 partial agonist, lead to the synthesis of a new series of N-anilinoethylamide derivatives, characterized by improved water solubility and increased metabolically stability. Different elements were considered for the optimization of this important classes of melatonergic ligands, including the study of the size and the orientation of substituents of the aromatic scaffold as well as the introduction of more hydrophilic groups, enhancing the water solubility, or protecting metabolically liable positions while preserving the high binding affinity and selectivity toward the MT2 receptor. Finally, dual MLT agonists-MAGL (monoacylglycerol lipase) inhibitors with suitable physicochemical properties have been obtained by fusion of the pharmacophore elements required at the two targets. The new dual-acting compounds displayed good to moderate activity at the melatonergic and endocannabinoid systems. The most active compound, resulting from the combination of N-anilinoethylamide scaffold with the O-hexafluoroisopropanol carbamate, is characterized by a balanced activity at both targets, and is currently under investigation for neuroprotective and anti-inflammatory effects in vivo.