- Demonstration of in Vitro Resurrection of Aged Acetylcholinesterase after Exposure to Organophosphorus Chemical Nerve Agents
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After the inhibition of acetylcholinesterase (AChE) by organophosphorus (OP) nerve agents, a dealkylation reaction of the phosphylated serine, referred to as aging, can occur. When aged, known reactivators of OP-inhibited AChE are no longer effective. Realkylation of aged AChE may provide a route to reversing aging. We designed and synthesized a library of quinone methide precursors (QMPs) as proposed realkylators of aged AChE. Our lead compound (C8) from an in vitro screen successfully resurrected 32.7 and 20.4% of the activity of methylphosphonate-aged and isopropyl phosphate-aged electric-eel AChE, respectively, after 4 days. C8 displays properties of both resurrection (recovery from the aged to the native state) and reactivation (recovery from the inhibited to the native state). Resurrection of methylphosphonate-aged AChE by C8 was significantly pH-dependent, recovering 21% of activity at 4 mM and pH 9 after only 1 day. C8 is also effective against isopropyl phosphate-aged human AChE.
- Zhuang, Qinggeng,Franjesevic, Andrew J.,Corrigan, Thomas S.,Coldren, William H.,Dicken, Rachel,Sillart, Sydney,Deyong, Ashley,Yoshino, Nathan,Smith, Justin,Fabry, Stephanie,Fitzpatrick, Keegan,Blanton, Travis G.,Joseph, Jojo,Yoder, Ryan J.,McElroy, Craig A.,Ekici, ?zlem Dogan,Callam, Christopher S.,Hadad, Christopher M.
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supporting information
p. 7034 - 7042
(2018/06/13)
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- HETEROAROMATIC ELECTROPHILES AND METHODS OF USING THEREOF
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Disclosed herein are compounds, compositions, and methods for reactivating or realkylating aged acetylcholinesterase inhibited by or conjugated to the organophosphorus compound. The organophosphorus compound can be a nerve agent. The acetylcholinesterase can be in the central nerve system (CNS) and/or the peripheral nervous system (PNS) of a subject. Accordingly, methods for ameliorating, diminishing, reversing, treating or preventing the toxic effects of an organophosphorus compound in a subject are provided herein. Methods for prophylactic or therapeutic treatment of exposure to an organophosphorus nerve agent are also provided.
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Page/Page column 49; 50; 55
(2018/09/18)
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- THIAZOLIDINONE COMPOUNDS AND USE THEREOF
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A pharmaceutical composition containing a compound of Formula (I) for treating an opioid receptor-associated condition. Also disclosed is a method for treating an opioid receptor-associated condition using such a compound. Further disclosed are two sets of thiazolidinone compounds of formula (I): (i) compounds each having an enantiomeric excess greater than 90% and (ii) compounds each being substituted with deuterium.
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Paragraph 1116-1117
(2017/09/21)
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