Dualsteric Muscarinic Antagonists鈥揙rthosteric Binding Pose Controls Allosteric Subtype Selectivity
详细信息 查看全文
- 作者：Jens Schmitz ; Dorina van der Mey ; Marcel Bermudez ; Jessica Kl枚ckner ; Ramona Schrage ; Evi Kostenis ; Christian Tr盲nkle ; Gerhard Wolber ; Klaus Mohr ; Ulrike Holzgrabe
- 刊名：Journal of Medicinal Chemistry
- 出版年：2014
- 出版时间：August 14, 2014
- 年：2014
- 卷：57
- 期：15
- 页码：6739-6750
- 全文大小：703K
- ISSN：1520-4804
文摘
Bivalent ligands of G protein-coupled receptors have been shown to simultaneously either bind to two adjacent receptors or to bridge different parts of one receptor protein. Recently, we found that bivalent agonists of muscarinic receptors can simultaneously occupy both the orthosteric transmitter binding site and the allosteric vestibule of the receptor protein. Such dualsteric agonists display a certain extent of subtype selectivity, generate pathway-specific signaling, and in addition may allow for designed partial agonism. Here, we want to extend the concept to bivalent antagonism. Using the phthal- and naphthalimide moieties, which bind to the allosteric, extracellular site, and atropine or scopolamine as orthosteric building blocks, both connected by a hexamethonium linker, we were able to prove a bitopic binding mode of antagonist hybrids for the first time. This is demonstrated by structure鈥揳ctivity relationships, site-directed mutagenesis, molecular docking studies, and molecular dynamics simulations. Findings revealed that a difference in spatial orientation of the orthosteric tropane moiety translates into a divergent M2/M5 subtype selectivity of the corresponding bitopic hybrids.