Martín Estrada1, Concepción Pérez1, Elena Soriano2, Erik Laurini3, Maurizio Romano4, Sabrina Pricl3,5, José A Morales-García6,7, Ana Pérez-Castillo6,7, María Isabel Rodríguez-Franco1. 1. Instituto de Química Médica (IQM-CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain. 2. Instituto de Química Orgánica General (IQOG-CSIC), C/Juan de la Cierva 3, 28006-Madrid, Spain. 3. Molecular Simulation Engineering (MOSE) Laboratory, DEA, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy. 4. Department of Life Sciences, University of Trieste, Via A. Valerio 28, 34127 - Trieste, Italy. 5. National Interuniversity Consortium for Material Science & Technology (INSTM), Research Unit MOSE-DEA, University of Trieste, Trieste, Italy. 6. Instituto de Investigaciones Biomédicas "Alberto Sols" (IIB-CSIC), C/Arturo Duperier 4, 28029-Madrid, Spain. 7. Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), C/Valderrebollo 5, 28031-Madrid, Spain.
Abstract
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: 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. CONCLUSION: 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.
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: 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. CONCLUSION: 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: Eva Mezeiova; Katarina Spilovska; Eugenie Nepovimova; Lukas Gorecki; Ondrej Soukup; Rafael Dolezal; David Malinak; Jana Janockova; Daniel Jun; Kamil Kuca; Jan Korabecny Journal: J Enzyme Inhib Med Chem Date: 2018-12 Impact factor: 5.051
Authors: Martín Estrada-Valencia; Clara Herrera-Arozamena; Concepción Pérez; Dolores Viña; José A Morales-García; Ana Pérez-Castillo; Eva Ramos; Alejandro Romero; Erik Laurini; Sabrina Pricl; María Isabel Rodríguez-Franco Journal: J Enzyme Inhib Med Chem Date: 2019-12 Impact factor: 5.051
Authors: Winnie Deuther-Conrad; Daniel Diez-Iriepa; Isabel Iriepa; Francisco López-Muñoz; María Angeles Martínez-Grau; Michael Gütschow; José Marco-Contelles Journal: RSC Med Chem Date: 2021-05-20