Pegoli, Andrea and Wifling, David and Gruber, Corinna G. and She, Xueke and Huebner, Harald and Bernhardt, Guenther and Gmeiner, Peter and Keller, Max (2019) Conjugation of Short Peptides to Dibenzodiazepinone-Type Muscarinic Acetylcholine Receptor Ligands Determines M2R Selectivity. JOURNAL OF MEDICINAL CHEMISTRY, 62 (11). pp. 5358-5369. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)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): pK(i) (hM(2)R) of 8.97, ratio of K-i 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.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | MOLECULAR-DYNAMICS SIMULATIONS; PROTEIN-COUPLED RECEPTOR; ALLOSTERIC MODULATION; ANTAGONISTS; BINDING; AGONISTS; DESIGN; |
| 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: | 06 Apr 2020 11:30 |
| Last Modified: | 06 Apr 2020 11:30 |
| URI: | https://pred.uni-regensburg.de/id/eprint/26834 |
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