| Affiliation: | 1. Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
These authors contributed equally to this work.;2. Institute of Pharmacy, Freie Universität Berlin, Königin-Luise-Strasse 2+4, 14195 Berlin, Germany;3. Pharmazeutische und Medizinische Chemie, Institut für Pharmazie und Lebensmittelchemie, Julius-Maximilians-Universität Würzburg, Am Hubland, 97074 Würzburg, Germany;4. Pharmacology and Toxicology, Institute of Pharmacy, University of Bonn, Gerhard-Domagk-Strasse 3, 53121 Bonn, Germany;5. Institute of Pharmacy, University of Regensburg, 93053 Regensburg, Germany |
| Abstract: | 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)-1H-benzod]imidazol-2(3H)-one] as M1-selective putative bitopic ligands, and derivatives of benzyl quinolone carboxylic acid (BQCA) as an M1 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. |
