Selective acetylcholinesterase inhibitors derived from muscle relaxant dantrolene |
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| Affiliation: | 1. Drug Metabolism and Toxicology, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan;2. WPI Nano Life Science Institute, Kanazawa University, Kanazawa, Japan;3. Synthetic Polymer Chemistry, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan;4. Department of Chemistry, Washington State University, Pullman, WA, United States;5. Synthetic Organic Chemistry, Faculty of Pharmaceutical Sciences, Kanazawa University, Kanazawa, Japan;1. Department of Chemistry and Pharmaceutical Sciences, Piazzale Europa 1, University of Trieste, 34127 Trieste, Italy;2. Department of Life Sciences, Via Valerio 28/1, University of Trieste, 34127 Trieste, Italy;1. School of Pharmacy, Jinan University, Guangzhou 510632, China;2. YZ Health-tech Inc., Hengqin District, Zhuhai 519000, China;3. School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China;4. Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China;5. Jeffrey Cheah School of Medicine and Health Sciences, Monash University Malaysia, Bandar Sunway 47500, Selangor Darul Ehsan, Malaysia;1. Key Laboratory of Eco-Environment-Related Polymer Materials, Ministry of Education of China, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, PR China;2. Key Laboratory of Polymer Materials of Gansu Province, College of Chemistry and Chemical Engineering, Northwest Normal University, Lanzhou, Gansu 730070, PR China;1. Department of Physicochemical Drug Analysis, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;2. Department of Technology and Biotechnology of Drugs, Jagiellonian University Medical College, Medyczna 9, 30-688 Krakow, Poland;3. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaetsstr. 1, Duesseldorf 40225, Germany |
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| Abstract: | Dantrolene, the only therapeutic agent for malignant hyperthermia, is known to have not only a muscle relaxant effect, but also a neuroprotective effect and Alzheimer's disease improving effect. Recently, it has been reported that dantrolene has a weak inhibitory effect on acetylcholinesterase (AChE), which is a therapeutic drug target for Alzheimer's disease. Thus, we focused on developing of AChE inhibitors with benzylpiperidine/piperazine moieties that are based on the dantrolene skeleton. Several derivatives showed an inhibitory activity. Among them, ortho-nitro derivative 8c showed the most potent inhibitory activity with the IC50 value of 34.2 nM. Furthermore, Lineweaver-Burk plot analysis indicated that 8c is AChE-selective inhibitor, which shows only a weak inhibitory effect on butyrylcholinesterase (BuChE) and a non-competitive inhibition. |
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| Keywords: | Acetylcholinesterase Muscle relaxant Dantrolene Alzheimer's disease |
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