New neurogenic lipoic-based hybrids as innovative Alzheimer%26apos;s drugs with sigma-1 agonism and beta-secretase inhibition

作者：Estrada Martin; Perez Concepcion; Soriano Elena; Laurini Erik; Romano Maurizio; Pricl Sabrina; Morales Garcia Jose A; Perez Castillo Ana; Isabel Rodriguez Franco Maria

来源：Future Medicinal Chemistry, 2016, 8(11): 1191-1207.

DOI：10.4155/fmc-2016-0036

• acetylcholinesterase
• AChE
• AD
• Alzheimer's disease
• BACE1
• beta-secretase-1
• lipoic acid
• multi-target directed ligands
• N-benzylpiperidine
• N, N-dibenzyl(N-methyl) amine
• neurogenic properties
• sigma-1 receptor
• sigma 1R

Background: Neurogenic agents emerge as innovative drugs for the treatment of Alzheimer's disease (AD), whose pathological complexity suggests strengthening research in the multi-target directed ligands strategy. Results: By combining the lipoic acid structure with N-benzylpiperidine or N, N-dibenzyl(N-methyl) amine fragments, new multi-target directed ligands were obtained that act at three relevant targets in AD: sigma-1 receptor (sigma R-1), beta-secretase-1 (BACE1) and acetylcholinesterase (AChE). Moreover, they show potent neurogenic properties, good antioxidant capacity and favorable CNS permeability. Molecular modeling studies on AChE, sigma R-1 and BACE1 highlight relevant drug-protein interactions that may contribute to the development of new disease-modifying drugs. Conclusion: New lipoic-based sigma(1) agonists endowed with neurogenic, antioxidant, cholinergic and amyloid beta-peptide-reducing properties have been discovered for the potential treatment of AD.

• 出版日期2016-7