Discovery of New Classes of Compounds that Reactivate Acetylcholinesterase Inhibited by Organophosphates.
نویسندگان
چکیده
Acetylcholinesterase (AChE) that has been covalently inhibited by organophosphate compounds (OPCs), such as nerve agents and pesticides, has traditionally been reactivated by using nucleophilic oximes. There is, however, a clearly recognized need for new classes of compounds with the ability to reactivate inhibited AChE with improved in vivo efficacy. Here we describe our discovery of new functional groups--Mannich phenols and general bases--that are capable of reactivating OPC--inhibited AChE more efficiently than standard oximes and we describe the cooperative mechanism by which these functionalities are delivered to the active site. These discoveries, supported by preliminary in vivo results and crystallographic data, significantly broaden the available approaches for reactivation of AChE.
منابع مشابه
Docking Studies, Synthesis, and In-vitro Evaluation of Novel Oximes Based on Nitrones as Reactivators of Inhibited Acetylcholinesterase
Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineatcholinergic synapsesand terminates the cholinergic effects. Some chemical agents likeorganophosphorus compounds (OPCs) including nerve agents and pesticides react withacetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and resultin accumulation of acetylcholineand show toxic e...
متن کاملA comparison of the potency of trimedoxime and other currently available oximes to reactivate tabun-inhibited acetylcholinesterase and eliminate acute toxic effects of tabun.
Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates by its chemical structure and by the fact that tabun-inhibited acetylcholinesterase is extraordinarily difficult to reactivate. The potency of trimedoxime and ot...
متن کاملDocking Studies, Synthesis, and In-vitro Evaluation of Novel Oximes Based on Nitrones as Reactivators of Inhibited Acetylcholinesterase
Acetylcholinesterase has important role in synaptic cleft. It breaks down the acetylcholineatcholinergic synapsesand terminates the cholinergic effects. Some chemical agents likeorganophosphorus compounds (OPCs) including nerve agents and pesticides react withacetylcholinesteraseirreversibly. They inhibit normal biological enzyme action and resultin accumulation of acetylcholineand show toxic e...
متن کاملDevelopment of New Reactivators of Tabun Inhibited Acetylcholinesterase and the Evaluation of Their Efficacy by in Vitro and in Vivo Methods
Tabun (O-ethyl-N,N-dimethyl phosphoramidocyanidate) belongs to highly toxic organophosphorus compounds misused as chemical warfare agents for military as well as terroristic purposes. It differs from other highly toxic organophosphates by its chemical structure and by the fact that tabun-inhibited acetylcholinesterase is extraordinarily difficult to reactivate. The antidotal treatment of tabun ...
متن کاملReactivation of organophosphate inhibited acetylcholinesterase activity by α,ω-bis-(4-hydroxyiminomethylpyridinium)alkanes in vitro
In this article, we have followed up the relationship between the ability to reactivate acetylcholinesterase inhibited by organophosphorus compounds and the length of linking chain between two 4-hydroxyiminomethylpyridinium rings of acetylcholinesterase reactivators. α,ω-bis(4hydroxyiminomethylpyridinium) alkanes have been used as the tested acetylcholinesterase reactivators. These oximes diffe...
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ورودعنوان ژورنال:
- Chembiochem : a European journal of chemical biology
دوره 16 15 شماره
صفحات -
تاریخ انتشار 2015