title: Competition radioligand binding assays for the investigation of bispyridinium compound affinities to the human muscarinic acetylcholine receptor subtype 5 (hM(5) ).
abstract: 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 indicate that bispyridinium compounds interact with muscarinic acetylcholine receptors as well. The muscarinic M(5) receptor is not well investigated compared to other subtypes, but could be important in the search for new drugs for treating nerve agent poisoning. A set of bispyridinium compounds structurally related to SAD-128 were tested in competition binding experiments with recombinant human M(5) 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 indicate that interaction of bispyridinium compounds with muscarinic receptors may contribute to their therapeutic efficacy.
authors.affiliation: Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstrasse 11, Munich, Germany. KarinNiessen@bundeswehr.org
authors.forename: K V
authors.initials: KV
authors.lastname: Niessen
authors.forename: J E H
authors.initials: JE
authors.lastname: Tattersall
authors.forename: C M
authors.initials: CM
authors.lastname: Timperley
authors.forename: M
authors.initials: M
authors.lastname: Bird
authors.forename: C
authors.initials: C
authors.lastname: Green
authors.forename: H
authors.initials: H
authors.lastname: Thiermann
authors.forename: F
authors.initials: F
authors.lastname: Worek
mesh_terms: D001665:Binding Sites; D006801:Humans; D011726:Pyridinium Compounds / Q000737:chemistry* / Q000494:pharmacology*; D011869:Radioligand Assay; D043642:Receptor, Muscarinic M5 / Q000737:chemistry / Q000378:metabolism*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism
chemical_list: D011726:Pyridinium Compounds; D043642:Receptor, Muscarinic M5; D011994:Recombinant Proteins; C016845:SAD-128