Muscarinic allosteric modulators: atypical structure-activity-relationships in bispyridinium-type compounds.
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.
Institute of Pharmacy and Food Chemistry, University of Würzburg, Würzburg, Germany.
Ulf
U
Sürig
Klaudia
K
Gaal
Evi
E
Kostenis
Christian
C
Tränkle
Klaus
K
Mohr
Ulrike
U
Holzgrabe
D000494:Allosteric Regulation; D000818:Animals; D001667:Binding, Competitive; D066298:In Vitro Techniques; D018727:Muscarinic Antagonists / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D019832:N-Methylscopolamine; D011726:Pyridinium Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D021281:Quantitative Structure-Activity Relationship; D043585:Receptor, Muscarinic M2 / Q000187:drug effects* / Q000378:metabolism; D013552:Swine; D014316:Tritium
D018727:Muscarinic Antagonists; D011726:Pyridinium Compounds; D043585:Receptor, Muscarinic M2; D014316:Tritium; D019832:N-Methylscopolamine