piperidines and Organophosphate-Poisoning

Organophosphate compounds (OPCs) are commonly used as pesticides and were developed as nerve agents for chemical warfare. Exposure to OPCs results in toxicity due to their covalent binding and inhibition of acetylcholinesterase (AChE). Treatment for toxicity due to OPC exposure has been largely focused on the reactivation of AChE by oxime-based compounds via direct nucleophilic attack on the phosphorous center. However, due to the disadvantages to existing oxime-based reactivators for treatment of OPC poisoning, we considered non-oxime mechanisms of reactivation. A high throughput screen of compound libraries was performed to discover previously unidentified reactivation compounds, followed by studies on their analogs. In the process, we discovered multiple non-oxime classes of compounds, the most robust of which we have already reported [1]. Herein, we report other classes of compounds we identified in our screen that are efficient at reactivation. During biochemical characterization, we also found some compounds with other activities that may inspire novel therapeutic approaches to OPC toxicity. Specifically, we found compounds that [1] increase the rate of substrate hydrolysis by AChE and, [2] protect the enzyme from inhibition by OPC. Further, we discovered that a subset of reactivator compounds recover activity from both AChE and the related enzyme butyrylcholinesterase (BuChE). We now report these compounds, their activities and discuss how each relates to therapeutic approaches that would provide alternatives to traditional oxime-based reactivation.

Topics: Acetylcholinesterase; Butyrylcholinesterase; Cholinesterase Inhibitors; Cholinesterase Reactivators; Donepezil; High-Throughput Screening Assays; Humans; Hydrolysis; Imidazoles; Indans; Kinetics; Organophosphate Poisoning; Oximes; Piperazines; Piperidines; Pyridines; Structure-Activity Relationship

Nerve agents are highly toxic organophosphorus (OP) compounds. They inhibit acetylcholinesterase (AChE), an enzyme that hydrolyses acetycholine (ACh) in the nervous system. Pathophysiological changes caused by OP poisonings are primarily the consequence of surplus ACh on cholinergic receptors and in the central nervous system. Standard treatment of OP poisoning includes combined administration of carbamates, atropine, oximes and anticonvulsants. In order to improve therapy, new compounds have been synthesised and tested. Tenocyclidine (TCP) and its adamantane derivative 1-[2-(2-thienyl)-2-adamantyl] morpholine (TAMORF) have shown interesting properties against soman poisoning. In this study, we developed a qualitative GC-MS method to measure elimination of TCP and TAMORF through rat urine in order to learn more about the mechanisms through which TCP protects an organism from OP poisoning and to determine the duration of this protective effect. GC-MS showed that six hours after treatment with TCP, rat urine contained only its metabolite 1-thienylcyclohexene, while urine of rats treated with TAMORF contained both TAMORF and its metabolites.

Topics: Adamantane; Animals; Gas Chromatography-Mass Spectrometry; Male; Morpholines; Organophosphate Poisoning; Phencyclidine; Piperidines; Rats; Rats, Wistar; Thiophenes

Classical emergency treatment of organophosphate poisoning includes the combined administration of a cholinesterase reactivator (an oxime), a muscarinic cholinergic receptor antagonist (atropine) and a benzodiazepine anticonvulsant (diazepam). In subjects taking pyridostigmine and trained to autoadminister at least one autoinjector at the first signs of poisoning, classical emergency treatment ensures survival but only an antiglutamatergic compound like gacyclidine appears to be able to ensure optimal management of nerve agent poisoning in terms of rapid normalization of EEG activity, clinical recovery and total neuroprotection. All of this reinforces the therapeutical value of gacyclidine, which is in the process of approval for human use in France for treatment of head injury, as a central nervous system protective agent for the treatment of OP poisoning.

Topics: Atropine; Cholinesterase Reactivators; Cyclohexanes; Cyclohexenes; Electroencephalography; Excitatory Amino Acid Antagonists; Humans; Organophosphate Poisoning; Piperidines; Poisoning; Pyridostigmine Bromide; Self Administration

Mice and guinea pigs were intoxicated by three different organophosphates: DFP, paraoxon, and OMPA. After onset of intoxication the animals were treated by either a mixture of atropine plus obidoxim or dexetimide plus obidoxim. The combination of dexetimide plus reactivator proved to be superior to the combination of atropine plus reactivator in case of DFP intoxication. In guinea pig the LD50 of DFP could be increased from about 20 to 1300 micrometers/kg b.wt. by dexetimide plus obidoxim when applied after the onset of intoxication. Concerning the paraoxon intoxication both antidote mixtures were found to be equally potent, whereas the purely peripheral intoxication induced by OMPA could only be influenced to a minor degree. The tissue distribution of atropine and dexetimide differs markedly, dexetimide being accumulated faster and to a higher degree. Thus the higher penetration rate of dexetimide into the central nervous system is considered to be the reason of its superiority in the treatment of an organophosphate intoxication of rapid onset.

Topics: Animals; Atropine; Dexetimide; Diet; Guinea Pigs; Insecticides; Isoflurophate; Lethal Dose 50; Mice; Obidoxime Chloride; Organophosphate Poisoning; Organophosphorus Compounds; Paraoxon; Piperidines

Topics: Animals; Antidotes; Atropine; Dexetimide; Male; Mice; Organophosphate Poisoning; Piperidines; Pyridinium Compounds; Rats

The therapeutic effects of pipethanate (sycotrol) and two newly synthetized cholinolytics, DPX-8 and ANC-51, were compared with atropine in mice poisoned by DDVP, fluostigmine, phospholine, and paraoxon. The antagonistic activotagonistic activity of tested drugs against acetylcholine-induced contraction of rat ileum and oxotremorine-induced salivation and tremor in the mouse was also studied. The anticholinergic activity of pipethanate, DPX-8, and ANC-51 was weaker than that of atropine. However,the therapeutic effect of pipethanate was higher than that of atropine in mice poisoned by the organophosphates. DPX-8 and ANC-51 afforded a better antidotal effect than atropine only in DDVP-poisoned mice.

Topics: Animals; Antidotes; Atropine; Benzilates; Dichlorvos; Echothiophate Iodide; Isoflurophate; Lethal Dose 50; Mice; Muscle, Smooth; Organophosphate Poisoning; Oxotremorine; Paraoxon; Parasympatholytics; Piperidines; Rats