In Search of NPY Y4R Antagonists: Incorporation of Carbamoylated Arginine, Aza-Amino Acids, or d-Amino Acids into Oligopeptides Derived from the C-Termini of the Endogenous Agonists

URN to cite this document:

urn:nbn:de:bvb:355-epub-361124 Copy

DOI to cite this document:

10.5283/epub.36112 Copy

Kuhn, Kilian K. ; Littmann, Timo ; Dukorn, Stefanie ; Tanaka, Miho ; Keller, Max ; Ozawa, Takeaki ; Bernhardt, Günther ; Buschauer, Armin

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Date of publication of this fulltext: 29 Aug 2017 09:34

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Details

Item type:	Article
Journal or Publication Title:	ACS Omega
Publisher:	AMER CHEMICAL SOC
Place of Publication:	WASHINGTON
Volume:	2
Number of Issue or Book Chapter:	7
Page Range:	pp. 3616-3631
Date:	2017
Institutions:	Chemistry and Pharmacy > Institute of Pharmacy Chemistry and Pharmacy > Institute of Pharmacy > Pharmaceutical/Medicinal Chemistry II (Prof. Buschauer)
Identification Number:	Value Type 10.1021/acsomega.7b00451 DOI
Keywords:	Y-1 RECEPTOR ANTAGONISTS; NEUROPEPTIDE-Y; HIGH-AFFINITY; PANCREATIC-POLYPEPTIDE; PEPTIDE; LIGANDS; ANALOGS; IDENTIFICATION; LUMINESCENCE; INHIBITOR;
Dewey Decimal Classification:	600 Technology > 615 Pharmacy 500 Science > 540 Chemistry & allied sciences
Status:	Published
Refereed:	Yes, this version has been refereed
Created at the University of Regensburg:	Yes
Item ID:	36112

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Abstract

The cross-linked pentapeptides (2R, 7R)-diaminooctanedioyl- bis(Tyr-Arg-Leu-Arg-Tyr-amide) ((2R, 7R)BVD- 74D, (2R, 7R)-1) and octanedioyl-bis(Tyr-Arg-Leu-ArgTyr- amide) (2) as well as the pentapeptide Ac-Tyr-Arg-LeuArg- Tyr-amide (3) were previously described as neuropeptide Y Y-4 receptor (Y4R) partial agonists. Here, we report on a series of analogues of (2R, 7R)-1 and 2 in which Arg(2), ...

Abstract

The cross-linked pentapeptides (2R, 7R)-diaminooctanedioyl- bis(Tyr-Arg-Leu-Arg-Tyr-amide) ((2R, 7R)BVD- 74D, (2R, 7R)-1) and octanedioyl-bis(Tyr-Arg-Leu-ArgTyr- amide) (2) as well as the pentapeptide Ac-Tyr-Arg-LeuArg- Tyr-amide (3) were previously described as neuropeptide Y Y-4 receptor (Y4R) partial agonists. Here, we report on a series of analogues of (2R, 7R)-1 and 2 in which Arg(2), Leu(3), or Arg(4) were replaced by the respective aza-amino acids. The replacement of Arg(2) in 3 with a carbamoylated arginine building block and the extension of the N-terminus by an additional arginine led to the high-affinity hexapeptide Ac-Arg-Tyr-N-omega-[(4-aminobutyl) aminocarbonyl] Arg-Leu-Arg-Tyr-amide (35), which was used as a precursor for a D-amino acid scan. The target compounds were investigated for Y4R functional activity in assays with complementary readouts: aequorin Ca2+ and beta-arrestin 1 or beta-arrestin 2 assays. In contrast to the parent compounds, which are Y4R agonists, several ligands were able to suppress the effect elicited by the endogenous ligand pancreatic polypeptide and therefore represent a novel class of peptide Y4R antagonists.

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Metadata last modified: 25 Nov 2020 20:59

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