title: New neurogenic lipoic-based hybrids as innovative Alzheimer's drugs with σ-1 agonism and β-secretase inhibition.
abstract: 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 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: σ-1 receptor (σ1R), 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, σ1R and BACE1 highlight relevant drug-protein interactions that may contribute to the development of new disease-modifying drugs.
  
  
  
  New lipoic-based σ1 agonists endowed with neurogenic, antioxidant, cholinergic and amyloid β-peptide-reducing properties have been discovered for the potential treatment of AD.
authors.affiliation: Instituto de Química Médica (IQM-CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: Martín
authors.initials: M
authors.lastname: Estrada
authors.affiliation: Instituto de Química Médica (IQM-CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: Concepción
authors.initials: C
authors.lastname: Pérez
authors.affiliation: Instituto de Química Orgánica General (IQOG-CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Soriano
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.
authors.forename: Erik
authors.initials: E
authors.lastname: Laurini
authors.affiliation: Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 - Trieste, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Romano
authors.affiliation: Molecular Simulation Engineering (MOSE) Laboratory, DEA, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy.|National Interuniversity Consortium for Material Science & Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste, Italy.
authors.forename: Sabrina
authors.initials: S
authors.lastname: Pricl
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (IIB-CSIC), C/Arturo Duperier 4, 28029-Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031-Madrid, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: Morales-García
authors.affiliation: Instituto de Investigaciones Biomédicas "Alberto Sols" (IIB-CSIC), C/Arturo Duperier 4, 28029-Madrid, Spain.|Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031-Madrid, Spain.
authors.forename: Ana
authors.initials: A
authors.lastname: Pérez-Castillo
authors.affiliation: Instituto de Química Médica (IQM-CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain.
authors.forename: María Isabel
authors.initials: MI
authors.lastname: Rodríguez-Franco
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000975:Antioxidants / Q000737:chemistry / Q000494:pharmacology; D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D008055:Lipids / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D017480:Receptors, sigma / Q000819:agonists*; D000097605:Sigma-1 Receptor
chemical_list: D000110:Acetylcholinesterase; D053829:Amyloid Precursor Protein Secretases; D000975:Antioxidants; D016282:Aspartic Acid Endopeptidases; D004791:Enzyme Inhibitors; D008055:Lipids; D018696:Neuroprotective Agents; D017480:Receptors, sigma; D000097605:Sigma-1 Receptor; C509280:BACE1 protein, human
keywords: AChE; AD; Alzheimer's disease; BACE1; N,N-dibenzyl(N-methyl)amine; N-benzylpiperidine; acetylcholinesterase; lipoic acid; multi-target directed ligands; neurogenic properties; β-secretase-1; σ-1 receptor; σ1R