Acetylcholinesterase protection and the anti-diisopropylfluorophosphate efficacy of E2020.
The reversible noncovalent inhibitor of acetylcholinesterase (R,S)-1-benzyl-4-[(5,6-dimethoxy-1-indanon)-2-yl]-methylpiperidine hydrochloride (E2020) was shown to inhibit electric eel acetylcholinesterase with high affinity in a mixed competitive-non-competitive way (Ki = 8.2 nM; Ki' = 13 nM). The pretreatment of electric eel acetylcholinesterase with E2020 dose-dependently prevented the inactivation of the enzyme by 40 microM diisopropylfluorophosphate. The EC50 for this protective effect (95% confidence limits) was 85 (76-96) nM, whereas under the same conditions E2020 IC50 was 12.3 (9.6-16) nM. E2020 injected together with atropine sulfate (17.4 mg/kg) into mice at doses in the range of 1.04-6.24 mg/kg 15 min before diisopropylfluorophosphate, caused a dose-dependent increase in diisopropylfluorophosphate LD50, resulting in protection ratios varying from 3.1 to 9.2. The effectiveness of E2020 antidotal effect was inversely correlated to the time between pretreatment and diisopropylfluorophosphate administration, being maximal when E2020 was injected 15 min, and possibly less than 15 min, before poisoning. From these experiments it is concluded that E2020 exerts a protective action against acute diisopropylfluorophosphate-poisoning in the mouse, presumably by protecting acetylcholinesterase from irreversible inactivation by this agent.
Dipartimento di Farmacologia Preclinica e Clinica, Università di Firenze, Italy.
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A
Galli
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F
Mori
L
L
Benini
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Cacciarelli
D000110:Acetylcholinesterase / Q000378:metabolism*; D000122:Acetylthiocholine / Q000378:metabolism; D000818:Animals; D001285:Atropine / Q000494:pharmacology; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D000077265:Donepezil; D004593:Electrophorus; D006868:Hydrolysis; D007189:Indans / Q000494:pharmacology*; D007531:Isoflurophate / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D008297:Male; D051379:Mice; D010880:Piperidines / Q000494:pharmacology*
D002800:Cholinesterase Inhibitors; D007189:Indans; D010880:Piperidines; D007531:Isoflurophate; D000122:Acetylthiocholine; D001285:Atropine; D000077265:Donepezil; D000110:Acetylcholinesterase