New neurogenic lipoic-based hybrids as innovative Alzheimer's drugs with σ-1 agonism and β-secretase inhibition

• Published in: Future medicinal chemistry 2016-07, Vol.8 (11), p.1191-1207
• Main Authors: Estrada, Martín, Pérez, Concepción, Soriano, Elena, Laurini, Erik, Romano, Maurizio, Pricl, Sabrina, Morales-García, José A, Pérez-Castillo, Ana, Rodríguez-Franco, María Isabel
• Format: Article
• Language: English
• Subjects: acetylcholinesterase; Acetylcholinesterase - metabolism; AChE; Alzheimer Disease - drug therapy; Alzheimer Disease - metabolism; Alzheimer's disease; Amyloid Precursor Protein Secretases - antagonists & inhibitors; Amyloid Precursor Protein Secretases - metabolism; Antioxidants - chemistry; Antioxidants - pharmacology; Aspartic Acid Endopeptidases - antagonists & inhibitors; Aspartic Acid Endopeptidases - metabolism; BACE1; benzylpiperidine; dibenzyl; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Humans; Lipids - chemistry; Lipids - pharmacology; lipoic acid; methyl)amine; Molecular Structure; multi-target directed ligands; neurogenic properties; Neuroprotective Agents - chemistry; Neuroprotective Agents - pharmacology; Receptors, sigma - agonists; Sigma-1 Receptor; β-secretase-1; σ-1 receptor; σ1R
• ISSN: 1756-8919; 1756-8927
• DOI: 10.4155/fmc-2016-0036

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. By combining the lipoic acid structure with -benzylpiperidine or -dibenzyl( -methyl)amine fragments, new multi-target directed ligands were obtained that act at three relevant targets in AD: σ-1 receptor (σ R), β-secretase-1 (BACE1) and acetylcholinesterase (AChE). Moreover, they show potent neurogenic properties, good antioxidant capacity and favorable CNS permeability. Molecular modeling studies on AChE, σ R and BACE1 highlight relevant drug-protein interactions that may contribute to the development of new disease-modifying drugs. New lipoic-based σ agonists endowed with neurogenic, antioxidant, cholinergic and amyloid β-peptide-reducing properties have been discovered for the potential treatment of AD.