POTENT GASTRIN-RELEASING PEPTIDE (GRP) ANTAGONISTS DERIVED FROM GRP(19-27) WITH A C-TERMINAL DPRO-PSI[CH2NH]PHE-NH2 AND N-TERMINAL AROMATICRESIDUES

We have previously reported that octapeptides with a -DPro Psi[CH2NH]P he-NH2 C-terminus are potent GRP antagonists and have greatly enhanced in vivo stability. Now we report the detailed syntheses of such pepti des and additional attempts to further increase metabolic stability. R eplacement of the -DPro Psi[CH2NH]Phe-NH2 with a ''DPro-statine''-Phe- NH2 led to less potent antagonistic activity. The introduction of ThiA la and BzthAla, to replace His and Trp, respectively, did not increase activity. A series of analogs having different aromatic residues at t he 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 D Phe and D2Nal is tolerated. Even though none of these peptides have hi gher activity than the original lead peptide, they are potentially mor e metabolically stable.