Inhibition of acetylcholinesterase by chromophore-linked fluorophosphonates |
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Authors: | Lilu Guo Alirica I Suarez Michael R Braden John M Gerdes Charles M Thompson |
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Institution: | 1. Department of Chemistry, The University of Montana, Missoula, MT 59812, United States;2. Center for Structural and Functional Neuroscience, Department of Biomedical and Pharmaceutical Sciences, The University of Montana, Missoula, MT 59812, United States;3. Facultad de Farmacia, Universidad Central de Venezuela, Caracas VZ, United States;4. ATERIS Technologies, 901 N Orange Street, Missoula MT 59802, United States |
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Abstract: | Fluorophosphonate (FP) head groups were tethered to a variety of chromophores (C) via a triazole group and tested as FPC inhibitors of recombinant mouse (rMoAChE) and electric eel (EEAChE) acetylcholinesterase. The inhibitors showed bimolecular inhibition constants (ki) ranging from 0.3 × 105 M?1 min?1 to 10.4 × 105 M?1 min?1. When tested against rMoAChE, the dansyl FPC was 12.5-fold more potent than the corresponding inhibitor bearing a Texas Red as chromophore, whereas the Lissamine and dabsyl chromophores led to better anti-EEAChE inhibitors. Most inhibitors were equal or better inhibitors of rMoAChE than EEAChE. 3-Azidopropyl fluorophosphonate, which served as one of the FP head groups, showed excellent inhibitory potency against both AChE’s (? 1 × 107 M?1 min?1) indicating, in general, that addition of the chromophore reduced the overall anti-AChE activity. Covalent attachment of the dabsyl-FPC analog to rMoAChE was demonstrated using size exclusion chromatography and spectroscopic analysis, and visualized using molecular modeling. |
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