title: Cooperative interactions at M2 muscarinic acetylcholine receptors: structure/activity relationships in stepwise shortened bispyridinium- and bis(ammonio)alkane-type allosteric modulators.
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.
authors.affiliation: Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Bonn, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Gilsbach
authors.forename: Maren
authors.initials: M
authors.lastname: Grossmüller
authors.forename: Vildan
authors.initials: V
authors.lastname: Alptüzün
authors.forename: Ercin
authors.initials: E
authors.lastname: Erciyas
authors.forename: Christian
authors.initials: C
authors.lastname: Tränkle
authors.forename: Ulrike
authors.initials: U
authors.lastname: Holzgrabe
authors.forename: Klaus
authors.initials: K
authors.lastname: Mohr
mesh_terms: D000473:Alkanes / Q000494:pharmacology; D000494:Allosteric Regulation; D000818:Animals; D006352:Heart Ventricles; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism; D019832:N-Methylscopolamine / Q000378:metabolism; D011726:Pyridinium Compounds / Q000494:pharmacology; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic / Q000737:chemistry* / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013552:Swine
chemical_list: D000473:Alkanes; D011726:Pyridinium Compounds; D043585:Receptor, Muscarinic M2; D011976:Receptors, Muscarinic; D019832:N-Methylscopolamine