Estrada_2016_Future.Med.Chem_8_1191

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 (sigma1R), 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, sigma1R and BACE1 highlight relevant drug-protein interactions that may contribute to the development of new disease-modifying drugs. CONCLUSION: New lipoic-based sigma1 agonists endowed with neurogenic, antioxidant, cholinergic and amyloid beta-peptide-reducing properties have been discovered for the potential treatment of AD.