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O-[7-(1-Methylquinolinium)]-1,3,2-Dioxaphosphorinane 2-Oxide Iodide: A Reversible Anti-acetylcholinesterase and Irreversible Anti-butyrylcholinesterase Organophosphorus Ester
Authors:Y Ashani  D Levy
Institution:Israel Institute for Biological Research , P.O. Box 19, Ness-Ziona , Israel
Abstract:Abstract

Although cyclic organophosphates(OP) esters (I) and their open-chain analogs (II) demonstrate similar reactivity of a P atom towards nucleophilic  /></span> displacement in aqueous solutions, the open-chain analogs (II) are thousand times more active as inhibitors of acetylcholinesterase(AChE). In order to explain the poor anti-ChE activity of I, a covalent molecular combination,IV, of the cyclic phosphate and an extremely effective leaving group (III) was prepared and evaluated. The new compound, IV, was found to inhibit progressively horse-serum butyrylcholinesterase(BuChE)at t<sup>1/2</sup>=15 min.(2.9μM, pH 7.0, 25°) whereas no progressive inhibition could be demonstrated for eel AChE incubated for several hrs under the same experimental conditions.Eel AChE was inhibited reversibly by IV with affinity constant,KI=1.3×10<sup>?6</sup> M. These findings may suggest the following: <u class=a. In order to compensate for overcrowding of the AChE active-site by large substituents it is essential to maintain flexibility of the four ligands attached to the P atom. It is further infered that cyclization does not permit such flexibility. b. BuChE differ considerably from AChE in the ability of the enzyme to provide simultaneous four-site interaction with tetrahedral OP inhibitors.
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