Competition radioligand binding assays for the investigation of bispyridinium compound affinities to the human muscarinic acetylcholine receptor subtype 5 (hM5)

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Standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes lacks efficacy with some nerve agents. Promising in vitro and in vivo results were obtained with the bispyridinium compound SAD-128, which was partly attributed to its interaction with nicotinic acetylcholine receptors. Previous studies were indicated that bispyridinium compounds interact with muscarinic acetylcholine receptors as well. However, the muscarinic M5 receptor was not well investigated compared to other subtypes, but could be important in the search for new drugs for treating nerve agent poisoning. In this study a set of bispyridinium compounds structurally related to SAD-128 were tested in competition binding experiments with recombinant human M5 muscarinic acetylcholine receptors. Five of the six investigated bispyridinium compounds interacted with the orthosteric binding site, with affinities in the low micromolar range. These data indicated that interaction of bispyridinium compounds with muscarinic receptors might contribute to their therapeutic efficacy.

Authors: Niessen, K. V.; Tattersall, J. E. H.; Timperley, C. M.; Bird, M.; Green,C.; Thiermann, H.; Worek, F ;Full Source: Drug Testing and Analysis 2012, 4(3-4), 292-297 (English) ;