High Affinity Agonists of the Neuropeptide Y (NPY) Y4 Receptor Derived from the C-Terminal Pentapeptide of Human Pancreatic Polypeptide (hPP): Synthesis, Stereochemical Discrimination, and Radiolabeling

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• 作者：Kilian K. Kuhn ; Thomas Ertl ; Stefanie Dukorn ; Max Keller ; Günther Bernhardt ; Oliver Reiser ; Armin Buschauer
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：July 14, 2016
• 年：2016
• 卷：59
• 期：13
• 页码：6045-6058
• 全文大小：767K
• 年卷期：0
• ISSN：1520-4804

文摘

The diastereomeric mixture of d/l-2,7-diaminooctanedioyl-bis(YRLRY-NH₂) (BVD-74D, 2) was described in the literature as a high affinity Y₄ receptor agonist. Here we report on the synthesis and pharmacological characterization of the pure diastereomers (2R,7R)- and (2S,7S)-2 and a series of homo- and heterodimeric analogues in which octanedioic acid was used as an achiral linker. To investigate the role of the Arg residues, one or two arginines were replaced by Ala. Moreover, N^ω-(6-aminohexylaminocarbonyl)Arg was introduced as an arginine replacement (17). (2R,7R)-2 was superior to (2S,7S)-2 in binding and functional cellular assays and equipotent with 17. [³H]Propionylation of one amino group in the linker of (2R,7R)-2 or at the primary amino group in 17 resulted in high affinity Y₄R radioligands ([³H]-(2R,7R)-10, [³H]18) with subnanomolar K_d values.