Development of MS Binding Assays targeting the binding site of MB327 at the nicotinic acetylcholine receptor

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

doi:10.1016/j.toxlet.2017.11.013

Cited by 22 publications

(32 citation statements)

References 47 publications

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“…MS Binding Assays were performed with [ 2 H 6 ]MB327 as marker and nAChR‐enriched membranes, prepared from Torpedo californica electroplaque tissue, as previously described …”

Section: Methodsmentioning

confidence: 99%

“…MB327, however, needs to be applied at high concentration (100–200 μ m ) to achieve muscle force recovery in vitro . This low potency of MB327 is in line with a low binding affinity toward the nAChR (MB327: p K i =4.73±0.03), which was determined by MS Binding Assays previously developed by us . We were planning to develop compounds with increased affinity to the MB327 binding site.…”

Section: Introductionmentioning

confidence: 99%

“…[9] This low potency of MB327 is in line with al ow binding affinity toward the nAChR (MB327:p K i = 4.73 AE 0.03), which was determined by MS Binding Assays previously developed by us. [11] We were planning to develop compounds with increased affinity to the MB327b inding site. Assuming that an increase in affinity is paralleled by intrinsic activity,these compounds should display also ah igherp otencya sn AChRr e-sensitizers, hence, being more effective antidotes for the treatment of OPC poisoning.…”

Section: Introductionmentioning

confidence: 99%

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Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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The current standard therapy to counteract organophosphate intoxication is not effective in equal measure against all types of organophosphorus compounds (OPCs), as the outcome of oxime‐induced reactivation of inactivated acetylcholinesterase (AChE) strongly depends on the particular OPC. In case the reactivation is insufficient, acetylcholine concentrations that rise to pathophysiological levels force the nicotinic acetylcholine receptor (nAChR) into a desensitized state and hence a functionally inactive state. As a consequence, neurotransmission is irreversibly disrupted at the neuromuscular junction. Previous electrophysiological studies identified the symmetric bispyridinium compound 1,1′‐(propane‐1,3‐diyl)bis[4‐(tert‐butyl)pyridin‐1‐ium] diiodide (MB327) as a re‐sensitizer of the desensitized nAChR. MB327 is thereby capable of restoring the functional activity. Very recently, in silico modeling studies suggested non‐symmetric derivatives of MB327 as potential re‐sensitizers with enhanced binding affinity and thus possible enhanced efficacy. In this study, 26 novel non‐symmetric bispyridinium compounds and related derivatives were synthesized. For the synthesis of the highly polar target compounds in sufficient quantities, newly developed and highly efficient two‐step procedures were used. Compounds were characterized in terms of their binding affinity toward the MB327 binding site at the nAChR using recently developed mass spectrometry (MS) Binding Assays. Regarding structure–affinity relationships at the MB327 binding site, the presence of two quaternary aromatic nitrogen centers as well as pyridinium systems with a tert‐butyl group at the 4‐position or a NMe2 group at the 3‐ or 4‐positions appeared to be beneficial for high binding affinities.

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“…MS Binding Assays were performed with [ 2 H 6 ]MB327 as marker and nAChR‐enriched membranes, prepared from Torpedo californica electroplaque tissue, as previously described …”

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

et al. 2018

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“…Patch clamp studies using human α7 nAChRs revealed that the pharmacological profile of these substances is similar to that of PNU120596, a well‐known type II PAM selective for the α7 nAChRs 126,137 . Affinity binding experiments using mass spectrometric detection (MS binding assays) confirmed that MB327 and analogous structures bind to tangible binding sites 138 . Interestingly, almost all of these substances inhibited both nAChR activity and muscle‐restoring potency at high concentrations, which may indicate an additional inhibitory binding site with lower affinity 118 .…”

Section: Treatmentmentioning

confidence: 81%

“…126,137 Affinity binding experiments using mass spectrometric detection (MS binding assays) confirmed that MB327 and analogous structures bind to tangible binding sites. 138 Interestingly, almost all of these substances inhibited both nAChR activity and muscle-restoring potency at high concentrations, which may indicate an additional inhibitory binding site with lower affinity. 118 Docking studies revealed that MB327 possibly binds toward two potential binding sites, which are present inside the nAChR channel pore and were not identified until recently.…”

Section: Muscle Force Measurementsmentioning

confidence: 96%

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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Screening and Characterizing of GPCR –Ligand Interactions with Mass Spectrometry‐Based Technologies

Qin

Wang

2022

GPCRs as Therapeutic Targets

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Development of MS Binding Assays targeting the binding site of MB327 at the nicotinic acetylcholine receptor

Cited by 22 publications

References 47 publications

Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor

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

Screening and Characterizing of GPCR –Ligand Interactions with Mass Spectrometry‐Based Technologies

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