2. Academic Validation
  3. Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice

  • J Med Chem. 2021 Jan 14;64(1):812-839. doi: 10.1021/acs.jmedchem.0c01775.
Elisabet Viayna 1,  Nicolas Coquelle 2 3,  Monika Cieslikiewicz-Bouet 4,  Pedro Cisternas 5,  Carolina A Oliva 5,  Elena Sánchez-López 6 7,  Miren Ettcheto 7 8 9,  Manuela Bartolini 10,  Angela De Simone 11,  Mattia Ricchini 1,  Marisa Rendina 1,  Mégane Pons 4,  Omidreza Firuzi 12,  Belén Pérez 13,  Luciano Saso 14,  Vincenza Andrisano 15,  Florian Nachon 16,  Xavier Brazzolotto 16,  Maria Luisa García 6 7,  Antoni Camins 7 8,  Israel Silman 17,  Ludovic Jean 4,  Nibaldo C Inestrosa 5 18,  Jacques-Philippe Colletier 2,  Pierre-Yves Renard 4,  Diego Muñoz-Torrero 1
Affiliations

Affiliations

  • 1 Laboratory of Medicinal Chemistry (CSIC Associated Unit), Faculty of Pharmacy and Food Sciences, and Institute of Biomedicine (IBUB), University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
  • 2 Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS UMR 5075, F-38054 Grenoble, France.
  • 3 Large Scale Structures Group, Institut Laue-Langevin, F-38042 Grenoble Cedex 9, France.
  • 4 Normandie University, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), 76000 Rouen, France.
  • 5 Center of Aging and Regeneration UC (CARE-UC), Departamento de Biología Celular y Molecular, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Av. Libertador Bernardo O'Higgins 340, P.O. Box 114, 8331150 Santiago, Chile.
  • 6 Department of Pharmacy, Pharmaceutical Technology and Physical Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Nanoscience and Nanotechnology (IN2UB), University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
  • 7 Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, E-28031 Madrid, Spain.
  • 8 Department of Pharmacology, Toxicology and Therapeutic Chemistry, Faculty of Pharmacy and Food Sciences, and Institute of Neuroscience, University of Barcelona, Av. Joan XXIII 27-31, E-08028 Barcelona, Spain.
  • 9 Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili, E-43201 Reus, Spain.
  • 10 Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy.
  • 11 Department of Drug Science and Technology, University of Turin, I-10125 Torino, Italy.
  • 12 Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, PO Box 3288, 71345 Shiraz, Iran.
  • 13 Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193 Bellaterra, Barcelona, Spain.
  • 14 Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy.
  • 15 Department for Life Quality Studies, University of Bologna, Corso d'Augusto 237, I-47921 Rimini, Italy.
  • 16 Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées BP73, 91993 Brétigny sur Orge, France.
  • 17 Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel.
  • 18 Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, 6200000 Punta Arenas, Chile.
PMID: 33356266 DOI: 10.1021/acs.jmedchem.0c01775
Abstract

The combination of the scaffolds of the cholinesterase inhibitor huprine Y and the antioxidant capsaicin results in compounds with nanomolar potencies toward human acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) that retain or improve the antioxidant properties of capsaicin. Crystal structures of their complexes with AChE and BChE revealed the molecular basis for their high potency. Brain penetration was confirmed by biodistribution studies in C57BL6 mice, with one compound (5i) displaying better brain/plasma ratio than donepezil. Chronic treatment of 10 month-old APP/PS1 mice with 5i (2 mg/kg, i.p., 3 times per week, 4 weeks) rescued learning and memory impairments, as measured by three different behavioral tests, delayed the Alzheimer-like pathology progression, as suggested by a significantly reduced Aβ42/Aβ40 ratio in the hippocampus, improved basal synaptic efficacy, and significantly reduced hippocampal oxidative stress and neuroinflammation. Compound 5i emerges as an interesting anti-Alzheimer lead with beneficial effects on cognitive symptoms and on some underlying disease mechanisms.

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