Interaction of bispyridinium compounds with the orthosteric binding site of human alpha7 and Torpedo californica nicotinic acetylcholine receptors (nAChRs).

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Niessen KV, Tattersall JE, Timperley CM, Bird M, Green C, Seeger T, Thiermann H, Worek F

Interaction of bispyridinium compounds with the orthosteric binding site of human alpha7 and Torpedo californica nicotinic acetylcholine receptors (nAChRs).

Toxicol Lett. 2011 Sep 25;206(1):100-4. doi: 10.1016/j.toxlet.2011.06.009. Epub 2011 Jun 16.

PubMed ID

21703337 [ View in PubMed

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Abstract

Standard treatment of poisoning by organophosphorus (OP) nerve agents with atropine and oximes lacks efficacy with different nerve agents. A direct pharmacologic intervention at the nicotinic acetylcholine receptor (nAChR) was proposed as an alternative therapeutic approach and promising in vitro and in vivo results were obtained with the bispyridinium compound SAD-128. In addition, a number of SAD-128 analogues improved neuromuscular transmission of soman-poisoned diaphragms in vitro. We investigated the interaction of six of these SAD-128 analogues with the orthosteric binding site of the human alpha7 nAChR and Torpedo californica nAChR with a high-throughput assay using radioactive ligands. The determined affinity constants indicate a weak interaction of three test compounds (K(i) in the micromolar range) with both receptors, but no interaction could be recorded with the other three test compounds. The six SAD-128 analogues showed a low intrinsic inhibitory potency with human acetylcholinesterase (IC(5)(0) > 400 muM). In conclusion, the results of the present study do not indicate a correlation between the affinity to the orthosteric binding site and the functional improvement of neuromuscular transmission and it is assumed that other mechanisms contribute to the therapeutic effect of the tested compounds.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Epibatidine	Neuronal acetylcholine receptor subunit alpha-7	Protein	Humans	Unknown	Not Available	Details