Reactivators of Acetylcholinesterase Inhibited by Organophosphorus Nerve Agents

Abstract

Since the September 11, 2001, terrorist attacks in the United States, the specter of a chemical threat against civilian populations has renewed research interest in chemical warfare agents, their mechanisms of action, and treatments that reverse their effects. In this Account, we focus specifically on organophosphorus nerve agents (OPNAs). Although some OPNAs are used as pest control, the most toxic chemicals in this class are used as chemical warfare agents in armed conflicts. The acute toxicity of OPNAs results from the irreversible inhibition of acetylcholinesterase (AChE, EC 3.1.1.7) via the formation of a covalent P-O bond at the serine hydroxyl group in the enzyme active site. AChE breaks down the neurotransmitter acetylcholine at neuronal synapses and neuromuscular junctions. The irreversible inhibition of AChE causes the neurotransmitter to accumulate in the synaptic cleft, leading to overstimulation of cholinergic receptors, seizures, respiratory arrest, and death. The current treatment for OPNA poisoning combines an antimuscarinic drug (e.g., atropine), an anticonvulsant drug (e.g., diazepam), and an AChE reactivator of the pyridinium aldoxime family (pralidoxime, trimedoxime, obidoxime, HI-6, HLö-7). Because of their high nucleophilicity, oximes can displace the phosphyl group from the catalytic serine, thus restoring the enzyme's catalytic activity. During 50 years of research in the reactivator field, researchers have synthesized and tested numerous structural modifications of monopyridinium oximes and bispyridinium oximes. In the past decade, medicinal chemists have focused their research on the more efficient bispyridinium reactivators, but all known reactivators have several drawbacks. First, due to their permanent positive charge, they do not cross the blood-brain barrier (BBB) efficiently and do not readily reactivate AChE in the central nervous system. Second, no single oxime is efficient against a wide variety of OPNAs. Third, oximes cannot reactivate "aged" AChE. This Account summarizes recent strategies for the development of AChE reactivators capable of crossing the BBB. The use of nanoparticulate transport and inhibition of P-glycoprotein efflux pumps improves BBB transport of these AChE reactivators. Chemical modifications that increased the lipophilicity of the pyridinium aldoximes, the addition of a fluorine atom and the replacement of a pyridyl ring with a dihydropyridyl moiety, enhances BBB permeability. The glycosylation of pyridine aldoximes facilitates increased BBB penetration via the GLUT-1 transport system. The development of novel uncharged reactivators that can move efficiently across the BBB represents one of the most promising of these new strategies.

The Evaluation of Benefit of Newly Prepared Reversible Inhibitors of Acetylcholinesterase and Commonly Used Pyridostigmine as Pharmacological Pretreatment of Soman-Poisoned Mice

“…Sufficiently effective pretreatment is considered to be very important especially in the case of soman exposure because soman-induced deleterious effects are extraordinarily difficult to counteract due to very low reactivating efficacy of currently used oximes (14). The reason for the weak reactivating potency of the oximes is very rapid aging of phosphonylated AChE (15)(16).…”

Efficacy of the GluK1/AMPA Receptor Antagonist LY293558 against Seizures and Neuropathology in a Soman-Exposure Model without Pretreatment and its Pharmacokinetics after Intramuscular Administration

“…injection of 2 mg/kg atropine sulfate (Sigma, St. Louis, MO), a muscarinic receptor antagonist, as well as an i.p. injection of 125 mg/kg HI-6 (Starks Associates, Buffalo, NY), a bispyridinium oxime that reactivates inhibited AChE primarily in the periphery (Joosen et al, 2011;Mercey et al, 2012) to control the peripheral effects of soman and prevent death from respiratory suppression. Rats that were treated only with atropine and HI-6 comprised the SOMAN group.…”

Dose Dependent Prophylactic Efficacy of 6-Chlorotacrine in Soman-Poisoned Mice

“…The effective pharmacological pretreatment seems to be very important in the case of soman exposure because soman-induced deleterious effects are very difficult to counteract due to low reactivating efficacy of currently used oximes (17). The reason for the weak reactivating potency of the oximes is very rapid aging of phosphonylated AChE (18)(19).…”