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Cooperative Interactions at M2 Muscarinic Acetylcholine Receptors: Structure/Activity Relationships in Stepwise Shortened Bispyridinium- and Bis(Ammonio)Alkane-Type Allosteric Modulators

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Abstract

Muscarinic M2-receptors allow for divergent modes of allosteric action, depending on the structure of the allosteric modulator. Phthalimido-substituted bis(ammonio)alkane-type modulators belong to the common mode allosteric agents, whereas a physicochemically closely related bispyridinium-oxime with dichlorobenzyl-substituents at both ends is an atypical agent. Here, we compared the actions of stepwise shortened compounds composed of the phthalimido moiety and middle chains of either the bispyridinium- or the bis(ammonio)alkane-type. Allosteric interactions were measured in pig M2 receptors with the orthosteric probe [3H]N-methylscopolamine ([3H]NMS) to label the acetylcholine binding site of the receptors. Dissociation and equilibrium binding experiments revealed parallel structure/activity-relationships in both series of compounds with regard to the cooperativity of interaction with [3H]NMS and to the underlying binding affinities in radioligand-occupied and free receptors. In conclusion, the findings are in line with the hypothesis that the phthalimido-moiety, but not the middle chain, is pivotal for the topology of interaction with the M2-receptor protein.

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Authors and Affiliations

  1. Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany

    Ralf Gilsbach, Maren Großmüller, Christian Tränkle & Klaus Mohr

  2. Department of Pharmaceutical Chemistry, Ege University, Izmir, Turkey

    Vildan Alptüzün & Ercin Erciyas

  3. Institute of Pharmacy and Food Chemistry, University of Würzburg, Germany

    Ulrike Holzgrabe

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  1. Ralf Gilsbach
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  2. Maren Großmüller
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Gilsbach, R., Großmüller, M., Alptüzün, V. et al. Cooperative Interactions at M2 Muscarinic Acetylcholine Receptors: Structure/Activity Relationships in Stepwise Shortened Bispyridinium- and Bis(Ammonio)Alkane-Type Allosteric Modulators. Neurochem Res 28, 667–673 (2003). https://doi.org/10.1023/A:1022858414900

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