Oxime reactivators of acetylcholinesterase are commonly used to treat highly toxic organophosphate poisoning. They are effective nucleophiles that can restore the catalytic activity of acetylcholinesterase; however, their main limitation is the difficulty in crossing the blood-brain barrier (BBB) because of their strongly hydrophilic nature. Various approaches to overcome this limitation and enhance the bioavailability of oxime reactivators in the CNS have been evaluated; these include structural modifications, conjugation with molecules that have transporters in the BBB, bypassing the BBB through intranasal delivery, and inhibition of BBB efflux transporters. A promising approach is the use of nanoparticles (NPs) as the delivery systems. Studies using mesoporous silica nanomaterials, poly (L-lysine)-graft-poly(ethylene oxide) NPs, metallic organic frameworks, poly(lactic-co-glycolic acid) NPs, human serum albumin NPs, liposomes, solid lipid NPs, and cucurbiturils, have shown promising results. Some NPs are considered as nanoreactors for organophosphate detoxification; these combine bioscavengers with encapsulated oximes. This study provides an overview and critical discussion of the strategies used to enhance the bioavailability of oxime reactivators in the central nervous system.

• Keywords
• Acetylcholinesterase, Blood–brain barrier, Delivery system, Nanoparticle, Oxime, Reactivator,
• MeSH
• Acetylcholinesterase * MeSH
• Biological Availability MeSH
• Biological Transport MeSH
• Central Nervous System * MeSH
• Blood-Brain Barrier MeSH
• Humans MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Acetylcholinesterase * MeSH

The organophosphorus antidotes, so-called oximes, are able to restore the enzymatic function of acetylcholinesterase (AChE) or butyrylcholinesterase (BChE) via cleavage of organophosphate from the active site of the phosphylated enzyme. In this work, the charged pyridinium oximes containing thiocarboxamide moiety were designed, prepared and tested. Their stability and pKa properties were found to be analogous to parent carboxamides (K027, K048 and K203). The inhibitory ability of thiocarboxamides was found in low µM levels for AChE and high µM levels for BChE. Their reactivation properties were screened on human recombinant AChE and BChE inhibited by nerve agent surrogates and paraoxon. One thiocarboxamide was able to effectively restore function of NEMP- and NEDPA-AChE, whereas two thiocarboxamides were able to reactivate BChE inhibited by all tested organophosphates. These results were confirmed by reactivation kinetics, where thiocarboxamides were proved to be effective, but less potent reactivators if compared to carboxamides.

• Keywords
• Cholinesterase, inhibition, organophosphate, oxime, reactivation,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Butyrylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Molecular Structure MeSH
• Organophosphates chemical synthesis   chemistry   pharmacology   MeSH
• Oximes chemical synthesis   chemistry   pharmacology   MeSH
• Pyridinium Compounds chemical synthesis   chemistry   pharmacology   MeSH
• Sulfhydryl Compounds chemical synthesis   chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Butyrylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Organophosphates MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Sulfhydryl Compounds MeSH

In the present work, we performed a complementary quantum mechanical (QM) study to describe the mechanism by which deprotonated pralidoxime (2-PAM) could reactivate human (Homo sapiens sapiens) acetylcholinesterase (HssAChE) inhibited by the nerve agent VX. Such a reaction is proposed to occur in subsequent addition-elimination steps, starting with a nucleophile bimolecular substitution (SN2) mechanism through the formation of a trigonal bipyramidal transition state (TS). A near attack conformation (NAC), obtained in a former study using molecular mechanics (MM) calculations, was taken as a starting point for this project, where we described the possible formation of the TS. Together, this combined QM/MM study on AChE reactivation shows the feasibility of the reactivation occurring via attack of the deprotonated form of 2-PAM against the Ser203-VX adduct of HssAChE.

• Keywords
• 2-PAM, QM/MM method, VX, acetylcholinesterase,
• MeSH
• Acetylcholinesterase chemistry   drug effects   MeSH
• Catalytic Domain MeSH
• Quantum Theory MeSH
• Humans MeSH
• Molecular Conformation MeSH
• Organothiophosphorus Compounds pharmacology   MeSH
• Pralidoxime Compounds chemistry   pharmacology   MeSH
• Protons MeSH
• Serine chemistry   MeSH
• Molecular Dynamics Simulation MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Organothiophosphorus Compounds MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• Protons MeSH
• Serine MeSH
• VX MeSH Browser

7-methoxytacrine-4-pyridinealdoxime (7-MEOTA-4-PA, named hybrid 5C) is a compound formerly synthesized and evaluated in vitro, together with 4-pyridine aldoxime (4-PA) and commercial reactivators of acetylcholinesterase (AChE). This compound was designed with the purpose of being a prophylactic reactivator, capable of interacting with different subdomains of the active site of AChE. To investigate these interactions, theoretical results from docking were first compared with experimental data of hybrid 5C, 4-PA, and two commercial oximes, on the reactivation of human AChE (HssAChE) inhibited by VX. Then, further docking studies, molecular dynamics simulations, and molecular mechanics Poisson-Boltzmann surface area calculations, were carried out to investigate reactivation performances, considering the near attack conformation (NAC) approach, prior to the nucleophilic substitution mechanism. Our results helped to elucidate the interactions of such molecules with the different subdomains of the active site of HssAChE. Additionally, NAC poses of each oxime were suggested for further theoretical studies on the reactivation reaction.

• Keywords
• 7-MEOTA-4-PA, Acetylcholinesterase, NAC, VX, molecular modeling,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Cholinesterase Inhibitors chemical synthesis   chemistry   pharmacology   MeSH
• Humans MeSH
• Models, Molecular MeSH
• Molecular Structure MeSH
• Obidoxime Chloride chemistry   pharmacology   MeSH
• Organothiophosphorus Compounds chemistry   pharmacology   MeSH
• Oximes chemistry   pharmacology   MeSH
• Pralidoxime Compounds chemistry   pharmacology   MeSH
• Pyridines chemistry   pharmacology   MeSH
• Dose-Response Relationship, Drug MeSH
• Structure-Activity Relationship MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 7-methoxytacrine-4-pyridinealdoxime MeSH Browser
• Acetylcholinesterase MeSH
• Cholinesterase Inhibitors MeSH
• Obidoxime Chloride MeSH
• Organothiophosphorus Compounds MeSH
• Oximes MeSH
• pralidoxime MeSH Browser
• Pralidoxime Compounds MeSH
• pyridine-4-aldoxime MeSH Browser
• Pyridines MeSH
• VX MeSH Browser

The present work aimed to compare the small, neutral and monoaromatic oxime, isatin-3-oxime (isatin-O), to the commercial ones, pralidoxime (2-PAM) and obidoxime, in a search for a new potential reactivator for acetylcholinesterase (AChE) inhibited by the pesticide paraoxon (AChE/POX) as well as a novel potential scaffold for further synthetic modifications. The multicriteria decision methods (MCDM) allowed the identification of the best docking poses of those molecules inside AChE/POX for further molecular dynamic (MD) studies, while Ellman's modified method enabled in vitro inhibition and reactivation assays. In corroboration with the theoretical studies, our experimental results showed that isatin-O have a reactivation potential capable of overcoming 2-PAM at the initial moments of the assay. Despite not achieving better results than obidoxime, this molecule is promising for being an active neutral oxime with capacity of crossing the blood⁻brain barrier (BBB), to reactivate AChE/POX inside the central and peripheral nervous systems. Moreover, the fact that isatin-O can also act as anticonvulsant makes this molecule a possible multipotent reactivator. Besides, the MCDM method showed to be an accurate method for the selection of the best docking poses generated in the docking studies.

• Keywords
• Ellman’s method, TOPSIS-AHP, acetylcholinesterase, molecular modeling, multicriteria decision making, neutral oxime,
• MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Erythrocytes drug effects   enzymology   MeSH
• Models, Molecular * MeSH
• Molecular Structure MeSH
• Oximes chemistry   pharmacology   MeSH
• Paraoxon chemistry   pharmacology   MeSH
• Cholinesterase Reactivators chemistry   pharmacology   MeSH
• Molecular Dynamics Simulation MeSH
• Molecular Docking Simulation MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Cholinesterase Inhibitors MeSH
• Oximes MeSH
• Paraoxon MeSH
• Cholinesterase Reactivators MeSH

BACKGROUND: Pharmaceuticals with targets in the cholinergic transmission have been used for decades and are still fundamental treatments in many diseases and conditions today. Both the transmission and the effects of the somatomotoric and the parasympathetic nervous systems may be targeted by such treatments. Irrespective of the knowledge that the effects of neuronal signalling in the nervous systems may include a number of different receptor subtypes of both the nicotinic and the muscarinic receptors, this complexity is generally overlooked when assessing the mechanisms of action of pharmaceuticals. METHODS: We have search of bibliographic databases for peer-reviewed research literature focused on the cholinergic system. Also, we have taken advantage of our expertise in this field to deduce the conclusions of this study. RESULTS: Presently, the life cycle of acetylcholine, muscarinic receptors and their effects are reviewed in the major organ systems of the body. Neuronal and non-neuronal sources of acetylcholine are elucidated. Examples of pharmaceuticals, in particular cholinesterase inhibitors, affecting these systems are discussed. The review focuses on salivary glands, the respiratory tract and the lower urinary tract, since the complexity of the interplay of different muscarinic receptor subtypes is of significance for physiological, pharmacological and toxicological effects in these organs. CONCLUSION: Most pharmaceuticals targeting muscarinic receptors are employed at such large doses that no selectivity can be expected. However, some differences in the adverse effect profile of muscarinic antagonists may still be explained by the variation of expression of muscarinic receptor subtypes in different organs. However, a complex pattern of interactions between muscarinic receptor subtypes occurs and needs to be considered when searching for selective pharmaceuticals. In the development of new entities for the treatment of for instance pesticide intoxication, the muscarinic receptor selectivity needs to be considered. Reactivators generally have a muscarinic M2 receptor acting profile. Such a blockade may engrave the situation since it may enlarge the effect of the muscarinic M3 receptor effect. This may explain why respiratory arrest is the major cause for deaths by esterase blocking.

• Keywords
• Acetylcholine, acetylcholinesterase, muscarinic receptor subtypes, pharmacotherapy,
• MeSH
• Cholinesterase Inhibitors pharmacology   MeSH
• Receptor Cross-Talk drug effects   MeSH
• Humans MeSH
• Receptors, Muscarinic drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Cholinesterase Inhibitors MeSH
• Receptors, Muscarinic MeSH

The ability of two newly developed oximes (K305, K307) to protect tabun-poisoned rats from tabun-induced inhibition of brain acetylcholinesterase, acute neurotoxic signs and symptoms and brain damage was compared with that of the oxime K203 and trimedoxime. The reactivating and neuroprotective effects of the oximes studied combined with atropine on rats poisoned with tabun at a sublethal dose were evaluated. The reactivating efficacy of a newly developed oxime K305 is lower compared to the reactivating efficacy of the oxime K203 and trimedoxime while the ability of the oxime K307 to reactivate tabun-inhibited acetylcholinesterase (AChE) in the brain roughly corresponds to the reactivating efficacy of the oxime K203 and it is slightly lower compared to trimedoxime. In addition, only one newly developed oxime (K307) combined with atropine was able to markedly decrease tabun-induced neurotoxicity although it did not eliminate all tabun-induced acute neurotoxic signs and symptoms. These results correspond to the histopathological evaluation of tabun-induced brain damage. Therefore, the newly developed oximes are not suitable for the replacement of commonly used oximes (especially trimedoxime) in the treatment of acute tabun poisonings.

• Keywords
• acetylcholinesterase, functional observational battery, histopathology, neurotoxicity, oximes, rats, tabun,
• MeSH
• Acetylcholinesterase metabolism   MeSH
• Atropine therapeutic use   MeSH
• Chemical Warfare Agents poisoning   MeSH
• Humans MeSH
• Brain drug effects   enzymology   MeSH
• Neuroprotective Agents therapeutic use   MeSH
• Neurotoxicity Syndromes drug therapy   MeSH
• Organophosphates toxicity   MeSH
• Organophosphate Poisoning drug therapy   MeSH
• Oximes therapeutic use   MeSH
• Rats, Wistar MeSH
• Pyridinium Compounds therapeutic use   MeSH
• Cholinesterase Reactivators therapeutic use   MeSH
• Trimedoxime therapeutic use   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Acetylcholinesterase MeSH
• Atropine MeSH
• Chemical Warfare Agents MeSH
• Neuroprotective Agents MeSH
• Organophosphates MeSH
• Oximes MeSH
• Pyridinium Compounds MeSH
• Cholinesterase Reactivators MeSH
• tabun MeSH Browser
• Trimedoxime MeSH