Schramm, Simon and Agnetta, Luca and Bermudez, Marcel and Gerwe, Hubert and Irmen, Matthias and Holze, Janine and Littmann, Timo and Wolber, Gerhard and Traenkle, Christian and Decker, Michael (2019) Novel BQCA- and TBPB-Derived M-1 Receptor Hybrid Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism. CHEMMEDCHEM, 14 (14). pp. 1349-1358. ISSN 1860-7179, 1860-7187
Full text not available from this repository. (Request a copy)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-benzo[d]imidazol-2(3H)-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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | M1 MUSCARINIC AGONISTS; TARGET MAJOR HALLMARKS; ALZHEIMERS-DISEASE; ALLOSTERIC MODULATORS; BITOPIC LIGANDS; OPPORTUNITIES; PHARMACOLOGY; ACTIVATION; STRATEGIES; EMPHASIS; allostery; dualsteric ligands; GPCRs; muscarinic receptors; partial agonists |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 02 Apr 2020 12:42 |
| Last Modified: | 02 Apr 2020 12:42 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26626 |
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