High Affinity Agonists of the Neuropeptide Y (NPY) Y-4 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, Guenther, Reiser, Oliver, Buschauer, Armin
• Format: Journal Article
• Language: English
• Published: WASHINGTON Amer Chemical Soc 14.07.2016
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ACID-DERIVATIVES; POTENT; HYDROGENATION; PEPTIDES; LIGANDS; LUMINESCENCE; ANTAGONISTS; EXPRESSION; METATHESIS; FAMILY
• DOI: 10.1021/acs.jmedchem.6b00309
• ISSN: 0022-2623

The diastereomeric mixture of D/L-2,7-diaminooctanedioyl-bis(YRLRY-NH2) (BVD-74D, 2) was described in the literature as a high affinity Y-4 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-omega-(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. [H-3]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 ([H-3]-(2R,7R)-10, [H-3]18) with subnanomolar K-d values.