Replacement of Thr(32) and GIn(34) in the C-Terminal Neuropeptide Y Fragment 25-36 by cis-Cyclobutane and cis-Cyclopentane beta-Amino Acids Shifts Selectivity toward the Y-4 Receptor

Berlicki, Lukasz and Kaske, Melanie and Gutierrez-Abad, Raquel and Bernhardt, Guenther and Illa, Ona and Ortuno, Rosa M. and Cabrele, Chiara and Buschauer, Armin and Reiser, Oliver (2013) Replacement of Thr(32) and GIn(34) in the C-Terminal Neuropeptide Y Fragment 25-36 by cis-Cyclobutane and cis-Cyclopentane beta-Amino Acids Shifts Selectivity toward the Y-4 Receptor. JOURNAL OF MEDICINAL CHEMISTRY, 56 (21). pp. 8422-8431. ISSN 0022-2623, 1520-4804

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Abstract

Neuropeptide Y (NPY) and pancreatic polypeptide (PP) control central and peripheral processes by activating the G protein coupled receptors YxR (x = 1, 2, 4, 5). We present analogs of the C-terminal fragments 25-36 and 32-36 of NPY and PP containing (1R,2S)-cyclobutane (beta Cbu) or (1R,2S)cyclopentane (beta 6Cpe) fl-amino acids, which display exclusively Y4R affinity. In particular, [beta Cpe(34)]-NPY-(25-36) is a Y4R selective partial agonist (EC50 41 +/- 6 nM, E-max 71%) that binds Y4R with a K-i of 10 +/- 2 nM and a selectivity >100-fold relative to YiR ancrY2R and >50-fold relative to Y5R Comparably, [Y-32, beta Cpe(34)-NPY(PP)-(32-36) selectively binds and activates Y4R (EC50 94 +/- 21 nM, E-max 73%). The NMR structure of [beta Cpe(34)]NPY-(25-36) in dodecylphosphatidylcholine micelles shows a short helix at residues 27-32, while the C-terminal segment R-33 beta Cpe(34)R(35)Y(36) is extended. The biological properties of the,beta Cbu- or beta Cpe-containing NPY and PP C-terminal fragments encourage the future application of these beta-amino acids in the synthesis of selective Y4R ligands.

Item Type: Article
Uncontrolled Keywords: FOOD-INTAKE; NPY-RECEPTORS; HIGH-AFFINITY; PEPTIDE-YY; XPLOR-NIH; AGONIST; ANALOGS; FAMILY; DIPEPTIDES; DEPRESSION;
Subjects: 500 Science > 540 Chemistry & allied sciences
600 Technology > 615 Pharmacy
Divisions: Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)
Chemistry and Pharmacy > Institut für Organische Chemie > Lehrstuhl Prof. Dr. Oliver Reiser
Depositing User: Dr. Gernot Deinzer
Date Deposited: 25 Mar 2020 11:03
Last Modified: 25 Mar 2020 11:03
URI: https://pred.uni-regensburg.de/id/eprint/15675

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