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

• Published in: Journal of medicinal chemistry Vol. 59; no. 13; pp. 6045 - 6058
• Main Authors: Kuhn, Kilian K, Ertl, Thomas, Dukorn, Stefanie, Keller, Max, Bernhardt, Günther, Reiser, Oliver, Buschauer, Armin
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 14.07.2016
• Subjects: Amino Acid Sequence; Animals; Cell Line, Tumor; CHO Cells; Cricetulus; HEK293 Cells; Humans; Pancreatic Polypeptide - chemical synthesis; Pancreatic Polypeptide - chemistry; Pancreatic Polypeptide - pharmacology; Protein Precursors - chemical synthesis; Protein Precursors - chemistry; Protein Precursors - pharmacology; Receptors, Neuropeptide Y - agonists; Receptors, Neuropeptide Y - metabolism; Stereoisomerism
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/acs.jmedchem.6b00309

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.