title: Potent gastrin-releasing peptide (GRP) antagonists derived from GRP (19-27) with a C-terminal DPro psi [CH2NH]Phe-NH2 and N-terminal aromatic residues.
abstract: We have previously reported that octapeptides with a -DPro psi[CH2NH]Phe- NH2 C-terminus are potent GRP antagonists and have greatly enhanced in vivo stability. Now we report the detailed syntheses of such peptides and additional attempts to further increase metabolic stability. Replacement of the -DPro psi[CH2NH]Phe-NH2 with a "-DPro-statine"-Phe-NH2 led to less potent antagonistic activity. The introduction of ThiAla and BzthAla, to replace His and Trp, respectively, did not increase activity. A series of analogs having different aromatic residues at the N-terminal, other than 3-phenylpropionic acid, are equally potent. These residues show increased activity when hydrophilic substitutions are added to the aromatic ring. Replacement of the C-terminal Phe by DPhe and D2Nal is tolerated. Even though none of these peptides have higher activity than the original lead peptide, they are potentially more metabolically stable.
authors.affiliation: Organic Chemistry Division, Burroughs Wellcome Company, Research Triangle Park, North Carolina 27709.
authors.forename: J J
authors.initials: JJ
authors.lastname: Leban
authors.forename: A
authors.initials: A
authors.lastname: Landavazo
authors.forename: J D
authors.initials: JD
authors.lastname: McDermed
authors.forename: E J
authors.initials: EJ
authors.lastname: Diliberto
authors.forename: M
authors.initials: M
authors.lastname: Jansen
authors.forename: B
authors.initials: B
authors.lastname: Stockstill
authors.forename: F C
authors.initials: FC
authors.lastname: Kull
mesh_terms: D000595:Amino Acid Sequence; D019886:Gastrin-Releasing Peptide; D008969:Molecular Sequence Data; D009152:Mutagenicity Tests; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D010455:Peptides; D019886:Gastrin-Releasing Peptide