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Updated: Aug 9, 2026

Methods for the Discovery of Novel Compounds Modulating a Gamma-Aminobutyric Acid Receptor Type A Neurotransmission
Published on: August 16, 2018
Muscarinic allosteric modulators: atypical structure-activity-relationships in bispyridinium-type compounds
Ulf Sürig1, Klaudia Gaal, Evi Kostenis
1Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.
Abstract:
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 M2 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 M2 receptors, whose orthosteric site was blocked by [3H]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.
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