title: Inhibition of acetylcholinesterase by chromophore-linked fluorophosphonates.
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 (k(i)) ranging from 0.3 x 10(5)M(-1)min(-1) to 10.4 x 10(5)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 ( congruent with 1 x 10(7)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.
authors.affiliation: Department of Chemistry, The University of Montana, Missoula, MT 59812, United States.
authors.forename: Lilu
authors.initials: L
authors.lastname: Guo
authors.forename: Alirica I
authors.initials: AI
authors.lastname: Suarez
authors.forename: Michael R
authors.initials: MR
authors.lastname: Braden
authors.forename: John M
authors.initials: JM
authors.lastname: Gerdes
authors.forename: Charles M
authors.initials: CM
authors.lastname: Thompson
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism*; D000818:Animals; D001095:Arachidonic Acids / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051379:Mice; D063065:Organophosphonates / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D002800:Cholinesterase Inhibitors; D063065:Organophosphonates; C104810:methyl arachidonylfluorophosphonate; D011092:Polyethylene Glycols; D000110:Acetylcholinesterase; C018557:glycofurol