Premium
Synthesis of a Series of Non‐Symmetric Bispyridinium and Related Compounds and Their Affinity Characterization at the Nicotinic Acetylcholine Receptor
Author(s) -
Rappenglück Sebastian,
Sichler Sonja,
Höfner Georg,
Wein Thomas,
Niessen Karin V.,
Seeger Thomas,
Paintner Franz F.,
Worek Franz,
Thiermann Horst,
Wanner Klaus T.
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800539
Subject(s) - chemistry , pyridinium , acetylcholinesterase , nicotinic acetylcholine receptor , nicotinic agonist , stereochemistry , acetylcholine , binding site , neuromuscular junction , acetylcholine receptor , organophosphate , cholinergic , receptor , enzyme , pharmacology , biochemistry , neuroscience , medicinal chemistry , medicine , biology , pesticide , agronomy
The current standard therapy to counteract organophosphate intoxication is not effective in equal measure against all types of organophosphorus compounds (OPCs), as the outcome of oxime‐induced reactivation of inactivated acetylcholinesterase (AChE) strongly depends on the particular OPC. In case the reactivation is insufficient, acetylcholine concentrations that rise to pathophysiological levels force the nicotinic acetylcholine receptor (nAChR) into a desensitized state and hence a functionally inactive state. As a consequence, neurotransmission is irreversibly disrupted at the neuromuscular junction. Previous electrophysiological studies identified the symmetric bispyridinium compound 1,1′‐(propane‐1,3‐diyl)bis[4‐( tert ‐butyl)pyridin‐1‐ium] diiodide (MB327) as a re‐sensitizer of the desensitized nAChR. MB327 is thereby capable of restoring the functional activity. Very recently, in silico modeling studies suggested non‐symmetric derivatives of MB327 as potential re‐sensitizers with enhanced binding affinity and thus possible enhanced efficacy. In this study, 26 novel non‐symmetric bispyridinium compounds and related derivatives were synthesized. For the synthesis of the highly polar target compounds in sufficient quantities, newly developed and highly efficient two‐step procedures were used. Compounds were characterized in terms of their binding affinity toward the MB327 binding site at the nAChR using recently developed mass spectrometry (MS) Binding Assays. Regarding structure–affinity relationships at the MB327 binding site, the presence of two quaternary aromatic nitrogen centers as well as pyridinium systems with a tert ‐butyl group at the 4‐position or a NMe 2 group at the 3‐ or 4‐positions appeared to be beneficial for high binding affinities.