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J. Biol. Chem., Vol. 275, Issue 46, 36043-36048, November 17, 2000

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The First Selective Agonist for the Neuropeptide YY₅ Receptor Increases Food Intake in Rats^*

Chiara Cabrele, Michael Langer^§, Reto Bader, Heike A. Wieland^¶, Henri N. Doods^¶, Oliver Zerbe, and Annette G. Beck-Sickinger^§

From the  Department of Applied Biosciences, Federal Institute of Technology of Zurich, Winterthurerstrasse 190, 8057 Zurich, Switzerland, ^¶ Division of Preclinical Research, Boehringer Ingelheim Pharma KG, Birkendorferstrasse 65, 88397 Biberach, Germany, and ^§ Institute of Biochemistry, University of Leipzig, Talstrasse 33, D 04103 Leipzig, Germany

The first Y₅ receptor-selective analog of neuropeptide Y (NPY), [Ala³¹,Aib³²]NPY, has been developed and biologically characterized. Using competition binding assays on cell lines that express different Y receptors, we determined the affinity of this analog to be 6 nM at the human Y₅ receptor, >500 nM at the Y₁ and Y₂ receptors, and >1000 nM at the Y₄ receptor. Activity studies performed in vitro using a cAMP enzyme immunoassay, and in vivo using food intake studies in rats, showed that the peptide acted as an agonist. Further peptides obtained by the combination of the Ala³¹-Aib³² motif with chimeric peptides containing segments of NPY and pancreatic polypeptide displayed the same selectivity and even higher affinity (up to 0.2 nM) for the Y₅ receptor. In vivo administration of the new Y₅ receptor-selective agonists significantly stimulated feeding in rats. The NMR solution structures of NPY and [Ala³¹,Aib³²]NPY showed a different conformation in the C-terminal region, where the -helix of NPY was substituted by a more flexible, 3₁₀-helical turn structure.

This paper is dedicated to Prof. Horst Kessler, LTU, Munich, on the occasion of his 60th birthday.

The atomic coordinates and the structure factors (code 1FVN) have been deposited in the Protein Data Bank, Research Collaboratory for Structural Bioinformatics, Rutgers University, New Brunswick, NJ (http://www.rcsb.org/).

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