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Muscarinic Allosteric Modulators: Atypical Structure‐Activity‐Relationships in Bispyridinium‐type Compounds
Author(s) -
Sürig Ulf,
Gaal Klaudia,
Kostenis Evi,
Tränkle Christian,
Mohr Klaus,
Holzgrabe Ulrike
Publication year - 2006
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.200600005
Subject(s) - allosteric regulation , chemistry , muscarinic acetylcholine receptor , allosteric modulator , mutagenesis , receptor , stereochemistry , allosteric enzyme , structure–activity relationship , binding site , biophysics , biochemistry , pharmacology , in vitro , biology , mutation , gene
Allosteric modulators of receptor binding are known for a variety of membrane receptors. In case of muscarinic receptors, a considerable number of structurally divergent modulators have been described. For the M 2 receptor subtype which has a high sensitivity to allosteric modulation most of the allosteric agents bind to the common allosteric binding site of the receptor protein. In this study, a series of DUO compounds characterized by a bispyridinium middle chain and lateral benzyloximeether moieties of a systematically varied substitution pattern has been evaluated with regard to their allosteric potency to affect M 2 receptors, whose orthosteric site was blocked by [ 3 H] N ‐methylscopolamine. The variations in potency were found to be surprisingly small and the structure‐activity relationships of the DUO compounds diverged from those of correspondingly substituted hexamethonio‐type allosteric modulators. One has to conclude that DUO compounds bind in an “atypical” manner which is in agreement with recently reported side‐directed mutagenesis and molecular modeling studies.