Organophosphate (OP) poisoning is currently treated with atropine, oximes and benzodiazepines. The nicotinic signs, i.e., respiratory impairment, can only be targeted indirectly via the use of oximes as reactivators of OP-inhibited acetylcholinesterase. Hence, compounds selectively targeting nicotinic acetylcholine receptors (nAChRs) might fundamentally improve current treatment options. The bispyridinium compound MB327 has previously shown some therapeutic effect against nerve agents in vitro and in vivo. Nevertheless, compound optimization was deemed necessary, due to limitations (e.g., toxicity and efficacy). The current study investigated a series of 4-tert-butyl bispyridinium compounds and of corresponding bispyridinium compounds without substituents in a rat diaphragm model using an indirect field stimulation technique. The length of the respective linker influenced the ability of the bispyridinium compounds to restore muscle function in rat hemidiaphragms. The current data show structure-activity relationships for a series of bispyridinium compounds and provide insight for future structure-based molecular modeling.

21 Nov 2020·Toxicology Mechanisms and MethodsQ4 · MEDICINE

Influence of experimental end point on the therapeutic efficacy of the antinicotinic compounds MB408, MB442 and MB444 in treating nerve agent poisoned mice – a comparison with oxime-based treatment

Q4 · MEDICINE

Article

Author: Tattersall, John E. H. ; Green, A. Christopher ; Kassa, Jiri ; Bird, Mike ; Timperley, Christopher M.

Therapeutic efficacy of antidotal treatment of acute poisoning by nerve agents is generally assessed by the evaluation of LD₅₀ values of nerve agents over 24 h following poisoning without or with a single administration of antidotal treatment. In this study, LD₅₀ values of four nerve agents (sarin, soman, tabun and cyclosarin) for non-treated and treated poisoning were evaluated in mice for two experimental end points - 6 h and 24 h. While the efficacy of atropine or oxime-based antidotal treatment was the same regardless of the experimental end point, the therapeutic efficacy of all three newly developed bispyridinium non-oxime compounds (MB408, MB442, and MB444) was mostly slightly higher at the 6 h end point compared to the 24 h end point, although the therapeutic efficacy of MB compounds was not superior to oxime-based antidotal treatment. These results contrast with a study in guinea-pigs using a structurally-related compound, MB327, which showed a striking increase in protection at 6 h compared to 24 h. It is suggested that the disparity may be due to pharmacokinetic differences between the two animal species.

05 Jul 2019·The Journal of Organic ChemistryQ2 · CHEMISTRY

Modulation of Reduction Potentials of Bis(pyridinium)alkane Dications through Encapsulation within Cucurbit[7]uril

Q2 · CHEMISTRY

Article

Author: Ramamurthy, Vaidhyanathan ; Pattabiraman, Mahesh ; Tcyrulnikov, Nikolai A. ; Varadharajan, Ramkumar ; Tikhomirova, Anastasiia A. ; Wilson, R. Marshall

Supramolecular modulation of reduction potentials of two series of bis(pyridinium)alkane salts is described. Study of the encapsulation of bis(pyridinium)alkane guests within the CB[7] cavity revealed the critical influence of the linker length and the position of the heteroatom on the reduction potentials of encapsulated guests. CB[7] complexation of pyridinium salts induced reduction potential changes ranging between +50 and -430 mV. Noncovalent modulation of the electron-accepting ability of organic cations can be utilized in electron-transfer-initiated reactions.

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Indication	Highest Phase	Country/Location	Organization	Date
Organophosphate Poisoning	Preclinical	United Kingdom	The Defence Science & Technology Laboratory	05 Dec 2017

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