N-Terminus to Arginine Side-Chain Cyclization of Linear Peptidic Neuropeptide y Y4Receptor Ligands Results in Picomolar Binding Constants

Konieczny A, Conrad M, Ertl FJ, Gleixner J, Gattor AO, Grätz L, Schmidt MF, Neu E, Horn A, Wifling D, Gmeiner P, Clark T, Sticht H, Keller M (2021)

Publication Type: Journal article, Original article

Publication year: 2021

Journal

Journal of Medicinal Chemistry American Chemical Society

Book Volume: 64

Pages Range: 16746-16769

Journal Issue: 22

DOI: 10.1021/acs.jmedchem.1c01574

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 pKi 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.

Authors with CRIS profile

Marcus Conrad Professur für Bioinformatik Eduard Neu Lehrstuhl für Pharmazeutische Chemie Anselm Horn Erlangen National High Performance Computing Center (NHR@FAU) Timothy Clark Naturwissenschaftliche Fakultät Heinrich Sticht Professur für Bioinformatik

Involved external institutions

Universität Regensburg DE Germany (DE)

How to cite

APA:

Konieczny, A., Conrad, M., Ertl, F.J., Gleixner, J., Gattor, A.O., Grätz, L.,... Keller, M. (2021). N-Terminus to Arginine Side-Chain Cyclization of Linear Peptidic Neuropeptide y Y4Receptor Ligands Results in Picomolar Binding Constants. Journal of Medicinal Chemistry, 64(22), 16746-16769. https://dx.doi.org/10.1021/acs.jmedchem.1c01574

MLA:

Konieczny, Adam, et al. "N-Terminus to Arginine Side-Chain Cyclization of Linear Peptidic Neuropeptide y Y4Receptor Ligands Results in Picomolar Binding Constants." Journal of Medicinal Chemistry 64.22 (2021): 16746-16769.

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