Synthesis of a Series of Structurally Diverse MB327 Derivatives and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor. (1st August 2018)

• Record Type: Journal Article
• Authors: Rappenglück, Sebastian; Sichler, Sonja; Höfner, Georg; Wein, Thomas; Niessen, Karin V.; Seeger, Thomas; Paintner, Franz F.; Worek, Franz; Thiermann, Horst; Wanner, Klaus T.
• Is Part Of: ChemMedChem. Volume 13:Number 17(2018)
• Page Start: 1806
• Page End: 1816
• Publication Date: 2018-08-01
• Subjects: bispyridinium -- drug design -- MS Binding Assays -- nitrogen heterocycles -- re-sensitizers; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.201800325
• Languages: English
• ISSNs: 1860-7179

Abstract

Abstract: A novel series of 30 symmetric bispyridinium and related N ‐heteroaromatic bisquaternary salts with a propane‐1, 3‐diyl linker was synthesized and characterized for their binding affinity at theMB327 binding site of nicotinic acetylcholine receptor (nAChR) from Torpedo californica . Compounds targeting this binding site are of particular interest for research into new antidotes against organophosphate poisoning, as therapeutically active 4‐ tert ‐butyl‐substituted bispyridinium saltMB327 was previously identified as a nAChR re‐sensitizer. Efficient access to the target compounds was provided by newly developed methods enabling N‐alkylation of sterically hindered or electronically deactivated heterocycles exhibiting a wide variety of functional groups. Determination of binding affinities toward theMB327 binding site at the nAChR, using a recently developed mass spectrometry (MS)‐based Binding Assay, revealed that several compounds reached affinities similar to that ofMB327 (p K i =4.73±0.03). Notably, the newly prepared lipophilic 4‐ tert ‐butyl‐3‐phenyl‐substituted bispyridinium salt PTM0022 (3 h ) was found to have significantly higher binding affinity, with a p K i value of 5.16±0.07, thus representing considerable progress toward the development of more potent nAChR re‐sensitizers. Abstract : Toward potential antidotes against organophosphate poisoning: A series of new bisquaternary compounds was designed, synthesized, and characterized for their binding affinity toward the nicotinic acetylcholine receptor (nAChR) using our recently developed MS Binding Assays. New binders and important structural motifs were identified, thus laying the groundwork for structure–affinity relationship‐guided drug design of potential nAChR re‐sensitizers.