Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines M2R Selectivity
Pegoli A, Wifling D, Gruber CG, She X, Hübner H, Bernhardt G, Gmeiner P, Keller M (2019)
Publication Type: Journal article
Publication year: 2019
Journal
Book Volume: 62
Pages Range: 5358-5369
Journal Issue: 11
DOI: 10.1021/acs.jmedchem.8b01967
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.
Authors with CRIS profile
Harald Hübner
Lehrstuhl für Pharmazeutische Chemie
Peter Gmeiner
Lehrstuhl für Pharmazeutische Chemie
Additional Organisation(s)
Involved external institutions
Germany (DE)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.
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