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

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Discovery of a Potent Dual Inhibitor of Acetylcholinesterase and Butyrylcholinesterase with Antioxidant Activity that Alleviates Alzheimer-like Pathology in Old APP/PS1 Mice
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2020-12-28 , 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

Affiliation

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
Institut de Biologie Structurale, Université Grenoble Alpes, CEA, CNRS UMR 5075, F-38054 Grenoble, France
Large Scale Structures Group, Institut Laue-Langevin, F-38042 Grenoble Cedex 9, France
Normandie University, UNIROUEN, INSA Rouen, CNRS, COBRA (UMR 6014), 76000 Rouen, France
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
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
Biomedical Research Networking Centre in Neurodegenerative Diseases (CIBERNED), Institute of Health Carlos III, E-28031 Madrid, Spain
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
Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University Rovira i Virgili, E-43201 Reus, Spain
Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, Via Belmeloro 6, I-40126 Bologna, Italy
Department of Drug Science and Technology, University of Turin, I-10125 Torino, Italy
Medicinal and Natural Products Chemistry Research Center, Shiraz University of Medical Sciences, PO Box 3288, 71345 Shiraz, Iran
Department of Pharmacology, Therapeutics and Toxicology, Autonomous University of Barcelona, E-08193 Bellaterra, Barcelona, Spain
Department of Physiology and Pharmacology “Vittorio Erspamer”, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy
Department for Life Quality Studies, University of Bologna, Corso d’Augusto 237, I-47921 Rimini, Italy
Département de Toxicologie et Risques Chimiques, Institut de Recherche Biomédicale des Armées BP73, 91993 Brétigny sur Orge, France
Department of Neurobiology, Weizmann Institute of Science, 76100 Rehovot, Israel
Centro de Excelencia en Biomedicina de Magallanes (CEBIMA), Universidad de Magallanes, 6200000 Punta Arenas, Chile

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.

中文翻译：

发现具有抗氧化活性的强效乙酰胆碱酯酶和丁酰胆碱酯酶双重抑制剂，可减轻老APP / PS1小鼠的阿尔茨海默氏样病状

胆碱酯酶抑制剂huprine Y的支架和抗氧化剂辣椒素的组合产生对人乙酰胆碱酯酶（AChE）和丁酰胆碱酯酶（BChE）具有纳摩尔浓度的化合物，其保留或改善了辣椒素的抗氧化特性。它们与AChE和BChE的复合物的晶体结构揭示了其高效力的分子基础。通过C57BL6小鼠的生物分布研究证实了脑部渗透，其中一种化合物（5i）的脑/血浆比例优于多奈哌齐。用5i慢性治疗10个月大的APP / PS1小鼠（3 mg / kg，ip，每周3次，4周）通过三种不同的行为测试可以挽救学习和记忆障碍，延缓了阿尔茨海默氏病样的病理进展，提示Aβ42/Aβ40比例显着降低海马，改善了基础突触的功效，并大大减少了海马的氧化应激和神经炎症。化合物5i作为有趣的抗阿尔茨海默氏症药物而出现，对认知症状和某些潜在的疾病机制具有有益作用。

更新日期：2021-01-14

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