In vitro pharmacological characterization of the bispyridinium non-oxime compound MB327 and its 2- and 3-regioisomers

Niessen, Karin V.; Seeger, Thomas; Rappenglück, Sebastian; Wein, Thomas; Höfner, Georg; Wanner, Klaus T.; Thiermann, Horst; Worek, Franz

doi:10.1016/j.toxlet.2017.10.009

Cited by 21 publications

(26 citation statements)

References 46 publications

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“…Binding affinitiest oward the MB327 binding site at T. californica nAChRw ere determined in MS Binding Assays using [ 2 H 6 ]MB327 (46)a smarker (Table 5). Because the storage buffer, differing from the incubation buffer by the lacko f CaCl 2 ,w as also identical to the incubation buffer that had been used in [ 3 H]epibatidine binding studies, [18,38] which were conducted recently for characterization of bispyridinium compounds at the orthosteric binding site of the T. californica nAChR, it appeared obvious to choose this buffer for incubation in [ 2 H 6 ]MB327 MS Binding Assays as well. According to the corresponding experimental protocol, aliquotso f nAChR-enriched membranes, prepared from T. californica electroplaque tissue and frozen in storageb uffer (120 mm NaCl, 5mm KCl, 8.05 mm Na 2 HPO 4 ,a nd 1.95 mm NaH 2 PO 4 ,p H7.4) were thawed, directly diluted with incubation buffer,a nd incubated in the presence of the marker (and test compounds if required).…”

Section: Biological Evaluationmentioning

confidence: 99%

“…Despite the high reactivity of bistriflate 21,avariety of functional groups,t hat is, alkylarylethers (2a-c, 3e), nitrile (3d), halide (3a-c), terminal alkyne (3i), ester (3j), amide (3f), and even secondary (2d)a nd tertiary amino substituents (2e)w ere (Table 3) using our MS Binding Assaysy ieldedr eliable results, the triflate counterion was assumed to cause interference in electrophysiologicalm easurements on the SURFE 2 Rp latform. [38] Thus, we decidedt os ynthesize compounds of type IV with iodide instead of triflate counterions.…”

Section: Preparation Of the Target Compoundsmentioning

confidence: 99%

“…Both buffers-storage andi ncubation buffer-are almosti dentical in this assay,e xcept that the latter also contains 1mm CaCl 2 .W itht he aim to simplify the developed MS Binding Assays, we examined the possibility of using only one bufferf or the whole procedure, that is, for the storage of Torpedo membrane preparationsa sw ell as for incubation in the binding experiments described herein. Because the storage buffer, differing from the incubation buffer by the lacko f CaCl 2 ,w as also identical to the incubation buffer that had been used in [ 3 H]epibatidine binding studies, [18,38] which were conducted recently for characterization of bispyridinium compounds at the orthosteric binding site of the T. californica nAChR, it appeared obvious to choose this buffer for incubation in [ 2 H 6 ]MB327 MS Binding Assays as well. Hence, saturation and auto-competition experiments were conducted exactly as described previously, [24] but also using the storage buffer for incubation of binding samples.…”

Section: Biological Evaluationmentioning

confidence: 99%

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Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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A novel series of 30 symmetric bispyridinium and related N-heteroaromatic bisquaternary salts with a propane-1,3-diyl linker was synthesized and characterized for their binding affinity at the MB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica. Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4-tert-butyl-substituted bispyridinium salt MB327 was previously identified as a nAChR re-sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N-alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward the MB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)-based Binding Assay, revealed that several compounds reached affinities similar to that of MB327 (pK =4.73±0.03). Notably, the newly prepared lipophilic 4-tert-butyl-3-phenyl-substituted bispyridinium salt PTM0022 (3 h) was found to have significantly higher binding affinity, with a pK value of 5.16±0.07, thus representing considerable progress toward the development of more potent nAChR re-sensitizers.

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Section: Biological Evaluationmentioning

confidence: 99%

Section: Preparation Of the Target Compoundsmentioning

confidence: 99%

Section: Biological Evaluationmentioning

confidence: 99%

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Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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“…117 Therefore, it is conceivable that PAMs, by increasing active receptor states, could be a promising therapeutic approach. 118 Possible nAChR-active antidotes. According to the hypotheses presented above, different potential approaches are discussed here, mainly noncompetitive antagonism, allosteric modulation, and "false" transmission.…”

Section: Receptor-active Substancesmentioning

confidence: 99%

Diagnostics and treatment of nerve agent poisoning—current status and future developments

Amend¹,

Niessen²,

Seeger³

et al. 2020

Annals of the New York Academy of Sciences

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Although 193 states have committed to the Chemical Weapons Convention and 98% of the declared chemical weapons stockpiles have been destroyed so far, nerve agent poisoning remains a lingering threat. The recent dissemination of sarin in Syria, the assassination of Kim Jong-Nam in Malaysia, and the assault on Sergei Skripal in the United Kingdom underline the need for effective treatment. The current therapeutic options of a muscarinic receptor antagonist, an oxime, and an anticonvulsant have been unchanged for decades. Therefore, new therapeutic strategies, for example, bioscavengers and receptor-active substances, are promising concepts that have to be examined for their benefits and limitations. In order to facilitate rapid diagnosis in challenging clinical situations, point-of-care diagnostics and detection are of importance. Therapeutic guidance concerning the duration and success of the current oxime therapy via determination of the cholinesterase status can contribute to an optimal use of resources. In summary, the challenges of current and future therapies for nerve agent poisoning and key diagnostic devices will be discussed.

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“…Another interesting group of molecules under study comes from tert-butyrylpyridinium, with emphasis on 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium)di(iodide) (MB327). Niessen et al (2018)[76] studied the efficiency of MB327 and some of its regioisomers, finding some important results in soman-inhibited AChE reactivation. The chemical structures of ADOC and MB327 are displayed inFigure 11 Zhuang et al (2018) [77].…”

mentioning

confidence: 99%

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

et al. 2020

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Acetylcholinesterase (AChE) is the key enzyme responsible for deactivating the ACh neurotransmitter. Irreversible or prolonged inhibition of AChE, therefore, elevates synaptic ACh leading to serious central and peripheral adverse effects which fall under the cholinergic syndrome spectra. To combat the toxic effects of some AChEI, such as organophosphorus (OP) nerve agents, many compounds with reactivator effects have been developed. Within the most outstanding reactivators, the substances denominated oximes stand out, showing good performance for reactivating AChE and restoring the normal synaptic acetylcholine (ACh) levels. This review was developed with the purpose of covering the new advances in AChE reactivation. Over the past years, researchers worldwide have made efforts to identify and develop novel active molecules. These researches have been moving farther into the search for novel agents that possess better effectiveness of reactivation and broad-spectrum reactivation against diverse OP agents. In addition, the discovery of ways to restore AChE in the aged form is also of great importance. This review will allow us to evaluate the major advances made in the discovery of new acetylcholinesterase reactivators by reviewing all patents published between 2016 and 2019. This is an important step in continuing this remarkable research so that new studies can begin.

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In vitro pharmacological characterization of the bispyridinium non-oxime compound MB327 and its 2- and 3-regioisomers

Cited by 21 publications

References 46 publications

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

Diagnostics and treatment of nerve agent poisoning—current status and future developments

Trends in the Recent Patent Literature on Cholinesterase Reactivators (2016–2019)

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