Novel BQCA and TBPB derived M1 Receptor Hybrid-Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism.

Novel BQCA and TBPB derived M1 Receptor Hybrid-Ligands: Orthosteric Carbachol Differentially Regulates Partial Agonism.
ChemMedChem. 2019 Jun 05;:
Authors: Schramm S, Agnetta L, Bermudez M, Gerwe H, Littmann T, Irmen M, Holze J, Wolber G, Tränkle C, Decker M
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 according to their exemplary role for 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 M1-selective putatively bitopic, i.e. orthosteric/allosteric agonist, i.e. TBPBds, and a benzyl quinolone carboxylic acid derivative (BQCAd) 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 agonist or antagonist behavior, respectively. These findings may help to design biased signaling and/or different extents of efficacy.
PMID: 31166078 [PubMed - as supplied by publisher]

Source: ChemMedChem - June 4, 2019 Category: Chemistry Authors: Schramm S, Agnetta L, Bermudez M, Gerwe H, Littmann T, Irmen M, Holze J, Wolber G, Tränkle C, Decker M Tags: ChemMedChem Source Type: research