New Melatonin–N,N‑Dibenzyl(N‑methyl)amine Hybrids: Potent Neurogenic Agents with Antioxidant, Cholinergic, and Neuroprotective Properties as Innovative Drugs for Alzheimer’s Disease

• Published in: Journal of medicinal chemistry 2014-05, Vol.57 (9), p.3773-3785
• Main Authors: López-Iglesias, Beatriz, Pérez, Concepción, Morales-García, José A, Alonso-Gil, Sandra, Pérez-Castillo, Ana, Romero, Alejandro, López, Manuela G, Villarroya, Mercedes, Conde, Santiago, Rodríguez-Franco, María Isabel
• Format: Article
• Language: English
• Subjects: Alzheimer Disease - drug therapy; Antioxidants - pharmacology; Antioxidants - therapeutic use; Blood-Brain Barrier; Cell Line; Cholinesterase Inhibitors - pharmacology; Cholinesterase Inhibitors - therapeutic use; Humans; Inhibitory Concentration 50; Magnetic Resonance Spectroscopy; Melatonin - analogs & derivatives; Melatonin - chemistry; Melatonin - pharmacology; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Spectrometry, Mass, Electrospray Ionization
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm5000613

Here, we describe a new family of melatonin–N,N-dibenzyl(N-methyl)amine hybrids that show a balanced multifunctional profile covering neurogenic, antioxidant, cholinergic, and neuroprotective properties at low-micromolar concentrations. They promote maturation of neural stem cells into a neuronal phenotype and thus they could contribute to CNS repair. They also protect neural cells against mitochondrial oxidative stress, show antioxidant properties, and inhibit human acetylcholinesterase (AChE). Moreover, they displace propidium from the peripheral anionic site of AChE, preventing the β-amyloid aggregation promoted by AChE. In addition, they show low cell toxicity and can penetrate into the CNS. This multifunctional profile highlights these melatonin–N,N-dibenzyl(N-methyl)amine hybrids as useful prototypes in the research of innovative drugs for Alzheimer’s disease.