title: 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.
abstract: 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. [(3)H]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 ([(3)H]-(2R,7R)-10, [(3)H]18) with subnanomolar Kd values.
authors.affiliation: Institute of Pharmacy, University of Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Kilian K
authors.initials: KK
authors.lastname: Kuhn
authors.affiliation: Institute of Organic Chemistry, University of Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Ertl
authors.affiliation: Institute of Pharmacy, University of Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Dukorn
authors.affiliation: Institute of Pharmacy, University of Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Max
authors.initials: M
authors.lastname: Keller
authors.affiliation: Institute of Pharmacy, University of Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Günther
authors.initials: G
authors.lastname: Bernhardt
authors.affiliation: Institute of Organic Chemistry, University of Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Reiser
authors.affiliation: Institute of Pharmacy, University of Regensburg , Universitätsstraße 31, 93053 Regensburg, Germany.
authors.forename: Armin
authors.initials: A
authors.lastname: Buschauer
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D045744:Cell Line, Tumor; D003412:Cricetulus; D057809:HEK293 Cells; D006801:Humans; D010191:Pancreatic Polypeptide / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011498:Protein Precursors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D017476:Receptors, Neuropeptide Y / Q000819:agonists* / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: C043710:PPY protein, human; D011498:Protein Precursors; D017476:Receptors, Neuropeptide Y; C109491:neuropeptide Y4 receptor; D010191:Pancreatic Polypeptide