Pharmacokinetic profile and quantitation of protection against soman poisoning by the antinicotinic compound MB327 in the guinea-pig

Abstract

Current organophosphorus nerve agent medical countermeasures do not directly address the nicotinic effects of poisoning. A series of antinicotinic bispyridinium compounds has been synthesized in our laboratory and screened in vitro. Their actions can include open-channel block at the nicotinic receptor which may contribute to their efficacy. The current lead compound from these studies, MB327 1,1'-(propane-1,3-diyl)bis(4-tert-butylpyridinium) as either the diiodide (I2) or dimethanesulfonate (DMS) has been examined in vivo for efficacy against nerve agent poisoning. MB327 I2 (0-113mgkg(-1)) or the oxime HI-6 DMS (0-100mgkg(- 1)), in combination with atropine and avizafone (each at 3mgkg(-1)) was administered to guinea-pigs 1min following soman poisoning. Treatment increased the LD50 of soman in a dose-dependent manner. The increase was statistically significant (p<0.01) at the 33.9mgkg(-1) (MB327) or 30mgkg(-1) (HI-6) dose with a comparable degree of protection obtained for both compounds. Following administration of 10mgkg(-1) (i.m.), MB327 DMS reached plasma Cmax of 22μM at 12min with an elimination t1/2 of 22min. In an adverse effect study, in the absence of nerve agent poisoning, a dose of 100mgkg(-1) or higher of MB327 DMS was lethal to the guinea-pigs. A lower dose of MB327 DMS (30mgkg(-1)) caused flaccid paralysis accompanied by respiratory impairment. Respiration normalised by 30min, although the animals remained incapacitated to 4h. MB327 or related compounds may be of utility in treatment of nerve agent poisoning as a component of therapy with atropine, anticonvulsant and oxime, or alternatively as an infusion under medical supervision.

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

“…[35][36][37] However,when these reaction conditions were used for the synthesis of compounds of type I and II, in most cases, only an egligible conversion but substantive decomposition of reactants occurred. This is mainly attributed to the low reactivity of the alkyl halides, especially when sterically hindered 2-substituted pyridine derivativesw ere used (6,17,19,20). Besides, in case of N-alkylated 22 and 24,demethylationr eactions by iodide ions also occurred.…”

“…[15] Furthermore, Seeger et al found that MB327 restores soman-impaired neuromuscular transmission in human and rat respiratory musclep reparations at concentrations of 100-200 mm. [19] Therefore, the therapeutic window of MB327 is too narrow for administration in cases of OPC poisoning, and hence more potent and more selective nAChR re-sensitizersmustbed eveloped. 100 mm, [17,18] possibly leadingt oa dverse effects, if administeredi nv ivo.…”

“…100 mm, [17,18] possibly leadingt oa dverse effects, if administeredi nv ivo. [19] Therefore, the therapeutic window of MB327 is too narrow for administration in cases of OPC poisoning, and hence more potent and more selective nAChR re-sensitizersmustbed eveloped.…”

Evaluation of the Influence of Three Newly Developed Bispyridinium Anti‐nicotinic Compounds (MB408, MB442, MB444) on the Efficacy of Antidotal Treatment of Nerve Agent Poisoning in Mice

“…The addition of the bispyridinium non‐oxime MB327 to the antidotal treatment of acute nerve agent poisoning is consistently beneficial . Here, we have examined the related bispyridinium non‐oximes MB408 (C3), MB444 (C4) and MB442 (C5 linker), which have been shown to antagonize both muscle and neuronal nicotinic receptors .…”

“…It has also been suggested that these bispyridinium non-oximes possibly interact with nAChR subtypes as positive allosteric modulators [34]. The addition of the bispyridinium non-oxime MB327 to the antidotal treatment of acute nerve agent poisoning is consistently beneficial [20,21,25]. Here, we have examined the related bispyridinium non-oximes MB408 (C3), MB444 (C4) and MB442 (C5 linker), which have been shown to antagonize both muscle and neuronal nicotinic receptors [33].…”