Nicotinic Antagonists in the Treatment of Nerve Agent Intoxication

Sheridan, Robert D.; Smith, Andrew P.; Turner, Simon R.; Tattersall, J.E.H.

doi:10.1177/014107680509800307

Cited by 43 publications

(36 citation statements)

References 15 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As a competitive antagonist of mAChRs, atropine selectively counteracts overstimulation of this receptor. In contrast, an analogous application of nAChR antagonists to treat nAChR overstimulation is not feasible as their therapeutic window is too small and patients would need artificial ventilation . Here oxime reactivators of AChE as part of the treatment regimen come into play.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

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.

show abstract

Section: Introductionmentioning

confidence: 99%

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

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Nevertheless, subtype-selective antagonists are valuable tools to define the roles played by α7 nAChRs in the physiological and pathophysiological processes. Moreover, α7 nAChR selective antagonists recently have been explored as potential treatments for non-small cell lung cancer,15 and for organophosphorus nerve agent intoxication 16. Exposure to nerve agents, as part of military or terrorist activities, or due to chronic low-level exposure to pesticides, has devastating health consequences.…”

mentioning

confidence: 99%

Discovery of novel α7 nicotinic receptor antagonists

Peng

Zhang

Snyder

et al. 2010

Bioorganic & Medicinal Chemistry Letters

View full text Add to dashboard Cite

Two distinct families of small molecules were discovered as novel α7 nicotinic acetylcholine receptor (nAChR) antagonists by pharmacophore-based virtual screening. These novel antagonists exhibited selectivity for the neuronal α7 subtype over other nAChRs and good brain penetration. Neuroprotection was demonstrated by representative compounds 7i and 8 in a mouse seizure-like behavior model induced by the nerve agent diisopropylfluorophosphate (DFP). These novel nAChR antagonists have potential use as antidote for organophosphorus nerve agent intoxication. KeywordsNicotinic acetylcholine receptors; α7 antagonists; Pharmacophore; Neuroprotection Nicotinic acetylcholine receptors (nAChRs) belong to the Cys-loop subfamily of pentameric ligand-gated ion channels and can be classified into muscle-type and neuronal subtypes. The neuronal nAChRs comprise twelve subunits (α2-α10 and β2-β4) with different arrangements, while the muscle-type is consisted of four subunits in a single arrangement of α1γα1β1δ (γ is replaced by ε in the adult). 1 Two major neuronal receptors α4β2 and α7 have been identified in the central nervous system. 2,3 The neuronal α7 nAChR has been proposed as a potential therapeutic target for a broad range of neurodegenerative and psychiatric diseases, including Alzheimer's disease, schizophrenia, anxiety, and epilepsy. 4-8 A variety of selective partial and full agonists have been developed for the α7 nAChR as potential therapeutics. 4 Several α7 nAChR selective agonists (e.g., TC-5619 and MEM-3454) have advanced to clinical trials for Alzheimer's disease and schizophrenia. [9][10][11] Although extensive efforts have been taken to identify selective α7 nAChR agonists, the development of α7 selective antagonists is relatively limited. Naturally derived compounds have been reported as α7 selective antagonists. For example, the krait Bungarus multicinctus derived peptide toxin α-bungarotoxin (α-BTX) and the seeds of Delphinum isolated nonpetide toxin methyllycaconitine (MLA) are two frequently used α7 selective antagonists. 12,13 Unfortunately, α-BTX is a potent antagonist for muscle-type nAChRs as well, and both In our effort to search for novel α7 nAChR selective ligands, we developed three dimensional (3D) pharmacophore models and conducted ligand-based virtual screening. Six potent and selective α7 ligands were selected as the training set for the pharmacophore model (Fig. 1). [17][18][19][20] The structures of all compounds were built with Molecular Operating Environment (MOE). 21 Energy minimization was conducted for the protonated forms using AM1 since all these compounds could be protonated at physiological conditions (pH 7.4). Flexible structural alignments were performed to identify the common chemical features responsible for the α7 receptor binding using the Flexible Alignment module within MOE. This alignment method uses a stochastic search algorithm to simultaneously explore the conformation space of all compounds in the training set. This operation generated several scores to quan...

show abstract

“…Previous work in our laboratory indicated that some of the therapeutic effect of the bis-quaternary compounds may be unrelated to cholinesterase reactivation (via the oxime groups) and may instead be due to blockade of nicotinic ion channels at the neuromuscular junction [15,16]. The work reported here is part of a large programme to define molecular properties necessary to maximise this novel therapeutic action.…”

Section: Introductionmentioning

confidence: 83%