Bisquaternary dimers of strychnine and brucine. A new class of potent enhancers of antagonist binding to muscarinic M2 receptors.
Bisquaternary dimers of strychnine and brucine were synthesized and their allosteric effect on muscarinic acetylcholine M(2) receptors was examined. The compounds retarded the dissociation of the antagonist [(3)H]N-methylscopolamine ([(3)H]NMS) from porcine cardiac cholinoceptors. This action indicated ternary complex formation. All compounds exhibited higher affinity to the allosteric site of [(3)H]NMS-occupied M(2) receptors than the monomeric strychnine and brucine, while the positive cooperativity with NMS was fully maintained. SAR studies revealed the unchanged strychnine ring as an important structural feature for high allosteric potency.
Zlotos
D P
DP
Pharmaceutical Institute, University of Würzburg, Am Hubland, 97074 Würzburg, Germany. zlotos@pharmazie.uni-wuerzburg.de
Buller
S
S
Holzgrabe
U
U
Mohr
K
K
D000494:Allosteric Regulation; D000818:Animals; D019281:Dimerization; D008968:Molecular Conformation; D018727:Muscarinic Antagonists / Q000494:pharmacology; D019832:N-Methylscopolamine / Q000494:pharmacology; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000187:drug effects / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013331:Strychnine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism*; D013552:Swine
D018727:Muscarinic Antagonists; D043585:Receptor, Muscarinic M2; C083806:brucine; D013331:Strychnine; D019832:N-Methylscopolamine