Weinhart, Corinna G. and Wifling, David and Schmidt, Maximilian F. and Neu, Eduard and Hoering, Carina and Clark, Timothy and Gmeiner, Peter and Keller, Max (2021) Dibenzodiazepinone-type muscarinic receptor antagonists conjugated to basic peptides: Impact of the linker moiety and unnatural amino acids on M2R selectivity. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 213: 113159. ISSN 0223-5234, 1768-3254
Full text not available from this repository. (Request a copy)Abstract
The family of human muscarinic acetylcholine receptors (MRs) is characterized by a high sequence homology among the five subtypes (M1R-M5R), being the reason for a lack of subtype selective MR ligands. In continuation of our work on dualsteric dibenzodiazepinone-type M2R antagonists, a series of M2R ligands containing a dibenzodiazepinone pharmacophore linked to small basic peptides was synthesized (64 compounds). The linker moiety was varied with respect to length, number of basic nitrogens (0-2) and flexibility. Besides proteinogenic basic amino acids (Lys, Arg), shorter homologues of Lys and Arg, containing three and two methylene groups, respectively, as well as D-configured amino acids were incorporated. The type of linker had a marked impact on M2R affinity and also effected M2R selectivity. In contrast, the structure of the basic peptide rather determined M2R selectivity than M2R affinity. For example, the most M2R selective compound (UR-CG188, 89) with picomolar M2R affinity (pK(i) 9.60), exhibited a higher M2R selectivity (ratio of K-i M1R/M2R/M3R/M4R/M5R: 110:1:5200:55:2300) compared to the vast majority of reported M2R preferring MR ligands. For selected ligands, M2R antagonism was confirmed in a M2R miniG protein recruitment assay. (C) 2021 Elsevier Masson SAS. All rights reserved.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; Muscarinic acetylcholine receptors; Dibenzodiazepinone derivative; Peptide; MR subtype selectivity; M2R selectivity; Basic amino acid; Induced-fit docking; M2R antagonist |
| Subjects: | 600 Technology > 615 Pharmacy |
| Divisions: | Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer) |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 12 Sep 2022 04:25 |
| Last Modified: | 12 Sep 2022 04:25 |
| URI: | https://pred.uni-regensburg.de/id/eprint/47027 |
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