Tacrine–Melatonin Hybrids as Multifunctional Agents for Alzheimer's Disease, with Cholinergic, Antioxidant, and Neuroprotective Properties

• DOI: 10.1002/cmdc.200800414
• Publication Date: 2009-03-23T08:51:26Z
• Authors: María Isabel Fern...; Concepción Pérez; Nuria Eugenia Cam...; Juan Antonio Páez; Gema Cristina Gon...; Paola Usán; Esther García‐Pal...; Manuela G. López; Mercedes Villarroya; Antonio G. García; Ana Martínez; María Isabel Rodr...
• Keywords: 0301 basic medicine; drug design; Molecular Sequence Data; Cholinergic Agents; Antioxidants; Cell Line; 03 medical and health sciences; Alzheimer Disease; Catalytic Domain; Humans; Amino Acid Sequence; Cholinergic; Melatonin; Amyloid beta-Peptides; molecular modeling; Alzheimer's disease; Neuroprotection; 3. Good health; Neuroprotective Agents; Models, Chemical; Blood-Brain Barrier; Acetylcholinesterase; Tacrine; neuroprotection; Cholinesterase Inhibitors; Sequence Alignment

AbstractTacrine–melatonin hybrids are potential multifunctional drugs for Alzheimer's disease that may simultaneously palliate intellectual deficits and protect the brain against both β‐amyloid peptide and oxidative stress. Molecular modeling studies show that they target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. They are nontoxic and may be able to penetrate the CNS, according to in vitro PAMPA‐BBB assays.magnified imageTacrine–melatonin hybrids were designed and synthesized as new multifunctional drug candidates for Alzheimer's disease. These compounds may simultaneously palliate intellectual deficits and protect the brain against both β‐amyloid (Aβ) peptide and oxidative stress. They show improved cholinergic and antioxidant properties, and are more potent and selective inhibitors of human acetylcholinesterase (hAChE) than tacrine. They also capture free radicals better than melatonin. Molecular modeling studies show that these hybrids target both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. At sub‐micromolar concentrations they efficiently displace the binding of propidium iodide from the PAS and could thus inhibit Aβ peptide aggregation promoted by AChE. Moreover, they also inhibit Aβ self‐aggregation and display neuroprotective properties in a human neuroblastoma line against cell death induced by various toxic insults, such as Aβ25–35, H2O2, and rotenone. Finally, they exhibit low toxicity and may be able to penetrate the central nervous system according to an in vitro parallel artificial membrane permeability assay for the blood–brain barrier (PAMPA‐BBB).