The effect of oxime reactivators on muscarinic receptors: Functional and binding examinations

Soukup, Ondřej; Killi, Uday Kumar; Proška, Jan; Bratova, L.; Adem, Abdu; Jun, Daniel; Fusek, J.; Kuča, Kamil; Tobin, Gunnar

doi:10.1016/j.etap.2011.01.003

Cited by 16 publications

(6 citation statements)

References 25 publications

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“…Obidoxime has previously been shown to exert antimuscarinic effects, and it has been suggested that it preferentially inhibits muscarinic M2 receptors . However, its antimuscarinic effect is much lower than that of atropine . Also, the obidoxime functional effect seems to include esterase inhibition, which could occur at different concentrations and dose levels than the muscarinic receptor antagonism .…”

Section: Discussionmentioning

confidence: 99%

“…37 However, its antimuscarinic effect is much lower than that of atropine. 38 Also, the obidoxime functional effect seems to include esterase inhibition, which could occur at different concentrations and dose levels than the muscarinic receptor antagonism. 30 The pharmacological effects of oximes, tentatively oximes with more pronounced antimuscarinic and antinicotinic effect that are not connected with reactivation of AChE, have been suggested to enable new therapeutic possibilities.…”

Section: Discussionmentioning

confidence: 99%

“…18 A negative correlation between AChE inhibition and muscarinic receptor antagonism has been suggested, and obidoxime belongs to the group of AChE reactivators that exert a relatively marked muscarinic antagonism. 30,38 Previously, the inhibition of muscarinic receptor effects by obidoxime has been shown to be particularly obvious in the heart. 30 This was also confirmed in the current experiments ( Fig.…”

Section: Discussionmentioning

confidence: 99%

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In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat

Killi

Wsól

Soukup

et al. 2014

Clin Exp Pharma Physio

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Obidoxime, a weak acetylcholine-esterase (AChE) inhibitor, exerts muscarinic receptor antagonism with a significant muscarinic M2 receptor selective profile. The current examinations aimed to determine the functional significance of muscarinic M2 receptors in the state of AChE inhibition, elucidating muscarinic M2 and M3 receptor interaction. In the in vitro examinations, methacholine evoked concentration-dependent bladder contractile and atrial frequency inhibitory responses. Although atropine abolished both, methoctramine (1 μmol/L) only affected the cholinergic response in the atrial preparations. However, in the presence of methoctramine, physostigmine, an AChE inhibitor, increased the basal tension of the bladder strip preparations (+68%), as well as the contractile responses to low concentrations of methacholine (< 5 μmol/L; +90-290%). In contrast to physostigmine, obidoxime alone raised the basal tension (+58%) and the responses to low concentrations of methacholine (< 5 μmol/L; +80-450%). Physostigmine concentration-dependently increased methacholine-evoked responses, similarly to obidoxime at low concentrations. However, at large concentrations (> 5 μmol/L), obidoxime, because of its unselective muscarinic receptor antagonism, inhibited the methacholine bladder responses. In conclusion, the current results show that muscarinic M2 receptors inhibit muscarinic M3 receptor-evoked contractile responses to low concentrations of acetylcholine in the synaptic cleft. The muscarinic M2 and M3 receptor crosstalk could be a counteracting mechanism in the treatment of AChE inhibition when using reactivators, such as obidoxime.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat

Killi

Wsól

Soukup

et al. 2014

Clin Exp Pharma Physio

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“… References: a=[ 154 ] b=[ 155 ] c=[ 156 ] d=[ 157 ] e=[ 158 ] f=[ 159 ] g=[ 160 ] h=[ 161 ] i=[ 162 ] j=[ 163 ] k=[ 164 ] l=[ 165 ] m=[ 166 ] n=[ 167 ] o=[ 168 ] p=[ 169 ] q=[ 170 ] r=[ 171 ] s=[ 172 ] t=[ 173 ] u=[ 147 ] v=[ 174 ], w=[ 175 ] x=[ 176 ]. …”

Section: Fig (1)unclassified

Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment

Soukup

Winder

Killi

et al. 2017

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BackgroundPharmaceuticals 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.MethodsWe 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.ResultsPresently, 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.ConclusionMost 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.

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“…A more complex cholinergic effect involving the interaction with muscarinic and nicotinic receptors, choline reuptake and AChE itself has been discussed. [11][12][13] Various oxime derivatives have been used as important synthetic intermediates and have been applied in the preparation of many biologically active heterocyclic compounds. 14 Furthermore, oximes are generally characterized by other significant biological activities.…”

Section: Introductionmentioning

confidence: 99%

Assessment of DNA-binding affinity of cholinesterase reactivators and electrophoretic determination of their effect on topoisomerase I and II activity

et al. 2016

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In this paper, we describe the biochemical properties and biological activity of a series of cholinesterase reactivators (symmetrical bisquaternary xylene-linked compounds, K106-K114) with ctDNA. The interaction of the studied derivatives with ctDNA was investigated using UV-Vis, fluorescence, CD and LD spectrometry, and electrophoretic and viscometric methods. The binding constants K were estimated to be in the range 1.05 × 10(5)-5.14 × 10(6) M(-1) and the percentage of hypochromism was found to be 10.64-19.28% (from UV-Vis titration). The used methods indicate that the studied samples are groove binders. Electrophoretic methods proved that the studied compounds clearly influence calf thymus Topo I (at 5 μM concentration, except for compounds K107, K111 and K114 which were effective at higher concentrations) and human Topo II (K110 partially inhibited Topo II effects even at 5 μM concentration) activity.

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The effect of oxime reactivators on muscarinic receptors: Functional and binding examinations

Cited by 16 publications

References 25 publications

In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat

In vitro functional interactions of acetylcholine esterase inhibitors and muscarinic receptor antagonists in the urinary bladder of the rat

Acetylcholinesterase Inhibitors and Drugs Acting on Muscarinic Receptors- Potential Crosstalk of Cholinergic Mechanisms During Pharmacological Treatment

Assessment of DNA-binding affinity of cholinesterase reactivators and electrophoretic determination of their effect on topoisomerase I and II activity

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