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Novel BQCA‐ and TBPB‐Derived M 1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism
Author(s) -
Schramm Simon,
Agnetta Luca,
Bermudez Marcel,
Gerwe Hubert,
Irmen Matthias,
Holze Janine,
Littmann Timo,
Wolber Gerhard,
Tränkle Christian,
Decker Michael
Publication year - 2019
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900283
Subject(s) - allosteric regulation , chemistry , allosteric modulator , g protein coupled receptor , agonist , context (archaeology) , carbachol , partial agonist , muscarinic acetylcholine receptor , antagonist , linker , stereochemistry , ligand (biochemistry) , receptor , biochemistry , biology , computer science , paleontology , operating system
Recently, investigations of the complex mechanisms of allostery have led to a deeper understanding of G protein‐coupled receptor (GPCR) activation and signaling processes. In this context, muscarinic acetylcholine receptors (mAChRs) are highly relevant due to their exemplary role in the study of allosteric modulation. In this work, we compare and discuss two sets of putatively dualsteric ligands, which were designed to connect carbachol to different types of allosteric ligands. We chose derivatives of TBPB [1‐(1′‐(2‐tolyl)‐1,4′‐bipiperidin‐4‐yl)‐1 H ‐benzo[ d ]imidazol‐2(3 H )‐one] as M 1 ‐selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M 1 positive allosteric modulator, varying the distance between the allosteric and orthosteric building blocks. Luciferase protein complementation assays demonstrated that linker length must be carefully chosen to yield either agonist or antagonist behavior. These findings may help to design biased signaling and/or different extents of efficacy.