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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Authors: | Gilsbach Ralf Großmüller Maren Alptüzün Vildan Erciyas Ercin Tränkle Christian Holzgrabe Ulrike Mohr Klaus |
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Affiliation: | (1) Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany;(2) Department of Pharmaceutical Chemistry, Ege University, Izmir, Turkey;(3) Institute of Pharmacy and Food Chemistry, University of Würzburg, Germany |
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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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Keywords: | Muscarinic receptors allosteric interactions cooperativity structure/activity relationships |
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