Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines M2R Selectivity

Journal article


Publication Details

Author(s): Pegoli A, Wifling D, Gruber CG, She X, Hübner H, Bernhardt G, Gmeiner P, Keller M
Journal: Journal of Medicinal Chemistry
Publication year: 2019
Volume: 62
Journal issue: 11
Pages range: 5358-5369
ISSN: 0022-2623


Abstract

Muscarinic acetylcholine receptors (MRs), comprising five subtypes (M1R-M5R) in humans, exhibit a high degree of structural similarity. Therefore, subtype-selective MR agonists and antagonists are lacking. We present an approach to highly M2R-selective MR antagonists based on the conjugation of di- or tripeptides to M2R-preferring dibenzodiazepinone-type MR antagonists. M2R selectivity was dependent on the peptide sequence and on the type of linker. The introduction of basic amino acids resulted in improved M2R selectivity (e.g., UR-AP148 (48): pKi (hM2R) of 8.97, ratio of Ki M1R/M2R/M3R/M4R/M5R of 49:1:6500:60:400) compared to reported pyridobenzo- and dibenzodiazepinone-type MR ligands. A supposed dualsteric binding mode of the DIBA-peptide conjugates, such as 48, at MRs was supported by molecular dynamics simulations.


FAU Authors / FAU Editors

Gmeiner, Peter Prof. Dr.
Lehrstuhl für Pharmazeutische Chemie
Hübner, Harald Dr.
Lehrstuhl für Pharmazeutische Chemie


External institutions with authors

Universität Regensburg


How to cite

APA:
Pegoli, A., Wifling, D., Gruber, C.G., She, X., Hübner, H., Bernhardt, G.,... Keller, M. (2019). Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines M2R Selectivity. Journal of Medicinal Chemistry, 62(11), 5358-5369. https://dx.doi.org/10.1021/acs.jmedchem.8b01967

MLA:
Pegoli, Andrea, et al. "Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines M2R Selectivity." Journal of Medicinal Chemistry 62.11 (2019): 5358-5369.

BibTeX: 

Last updated on 2019-01-07 at 09:23