title: Dualsteric muscarinic antagonists--orthosteric binding pose controls allosteric subtype selectivity.
abstract: 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-activity 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.
authors: Institute of Pharmacy and Food Chemistry, University of Würzburg , Am Hubland, D-97074 Würzburg, Germany.
authors: Jens
authors: J
authors: Schmitz
authors: Dorina
authors: D
authors: van der Mey
authors: Marcel
authors: M
authors: Bermudez
authors: Jessica
authors: J
authors: Klöckner
authors: Ramona
authors: R
authors: Schrage
authors: Evi
authors: E
authors: Kostenis
authors: Christian
authors: C
authors: Tränkle
authors: Gerhard
authors: G
authors: Wolber
authors: Klaus
authors: K
authors: Mohr
authors: Ulrike
authors: U
authors: Holzgrabe
mesh_terms: D000494:Allosteric Regulation; D000818:Animals; D001286:Atropine Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D016466:CHO Cells; D003412:Cricetulus; D054314:Drug Inverse Agonism; D006801:Humans; D008968:Molecular Conformation; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D018721:Muscarinic Agonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018727:Muscarinic Antagonists / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D009154:Mutation; D053644:Naphthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010797:Phthalimides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011869:Radioligand Assay; D043585:Receptor, Muscarinic M2 / Q000819:agonists / Q000037:antagonists & inhibitors / Q000235:genetics; D012602:Scopolamine Derivatives / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D001286:Atropine Derivatives; D018721:Muscarinic Agonists; D018727:Muscarinic Antagonists; D053644:Naphthalimides; D010797:Phthalimides; D043585:Receptor, Muscarinic M2; D012602:Scopolamine Derivatives