Konieczny, Adam and Conrad, Marcus and Ertl, Fabian J. and Gleixner, Jakob and Gattor, Albert O. and Graetz, Lukas and Schmidt, Maximilian F. and Neu, Eduard and Horn, Anselm H. C. and Wifling, David and Gmeiner, Peter and Clark, Timothy and Sticht, Heinrich and Keller, Max (2021) N-Terminus to Arginine Side-Chain Cyclization of Linear Peptidic Neuropeptide Y Y-4 Receptor Ligands Results in Picomolar Binding Constants. JOURNAL OF MEDICINAL CHEMISTRY, 64 (22). pp. 16746-16769. ISSN 0022-2623, 1520-4804
Full text not available from this repository. (Request a copy)Abstract
The family of neuropeptide Y (NPY) receptors comprises four subtypes (Y1R, Y2R, Y4R, Y5R), which are addressed by at least three endogenous peptides, i.e., NPY, peptide YY, and pancreatic polypeptide (PP), the latter showing a preference for Y4R. A series of cyclic oligopeptidic Y4R ligands were prepared by applying a novel approach, i.e., N-terminus to arginine side-chain cyclization. Most peptides acted as Y4R partial agonists, showing up to 60-fold higher Y4R affinity compared to the linear precursor peptides. Two cyclic hexapeptides (18, 24) showed higher Y4R potency (Ca2+ aequorin assay) and, with pK(i) values >10, also higher Y4R affinity compared to human pancreatic polypeptide (hPP). Compounds such as 18 and 24, exhibiting considerably lower molecular weight and considerably more pronounced Y4R selectivity than PP and previously described dimeric peptidic ligands with high Y4R affinity, represent promising leads for the preparation of labeled tool compounds and might support the development of drug-like Y4R ligands.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | PANCREATIC-POLYPEPTIDE; MOLECULAR-DYNAMICS; CARBAMOYLATED ARGININE; FUNCTIONAL EXPRESSION; ALLOSTERIC SODIUM; AMINO ACIDS; FOOD-INTAKE; AFFINITY; CLONING; ANTAGONISTS; |
| 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: | 09 Sep 2022 06:32 |
| Last Modified: | 09 Sep 2022 06:32 |
| URI: | https://pred.uni-regensburg.de/id/eprint/46892 |
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