Muscarinic allosteric modulators: atypical structure-activity-relationships in bispyridinium-type compounds |
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Authors: | Sürig Ulf Gaal Klaudia Kostenis Evi Tränkle Christian Mohr Klaus Holzgrabe Ulrike |
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Institution: | Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany. |
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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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Keywords: | Bispyridinium‐type compounds Allosteric modulators M2‐receptors |
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