Carboxyl-terminal modification of a gastrin releasing peptide derivative generates potent antagonists.
Gastrin releasing peptide (GRP) is a 27-residue peptide hormone which is analogous to the amphibian peptide bombesin. GRP serves a variety of physiological functions and has been implicated as an autocrine factor in the growth regulation of small cell lung cancer cells. We have developed a series of potent GRP antagonists by modification of the COOH terminus of N-acetyl-GRP-20-27. The most potent member of this series, N-acetyl-GRP-20-26-OCH2CH3, exhibits an IC50 of 4 nM in a competitive binding inhibition assay. This compound blocks GRP-stimulated mitogenesis in Swiss 3T3 mouse fibroblasts, inhibits GRP-dependent release of gastrin in vitro, and blocks GRP-induced elevation of [Ca2+]i in H345 small cell lung cancer cells. These results demonstrate that while residues 20-27 of GRP influence binding of the parent peptide to its receptor, the COOH-terminal amino acid is primarily responsible for triggering the subsequent biological response.
Heimbrook
D C
DC
Department of Cancer Research, Merck Sharp and Dohme Research Laboratories, West Point, Pennsylvania 19486.
Saari
W S
WS
Balishin
N L
NL
Friedman
A
A
Moore
K S
KS
Reimen
M W
MW
Kiefer
D M
DM
Rotberg
N S
NS
Wallen
J W
JW
Oliff
A
A
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin; D002118:Calcium / Q000378:metabolism; D018288:Carcinoma, Small Cell / Q000378:metabolism; D005260:Female; D019886:Gastrin-Releasing Peptide; D005755:Gastrins / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000494:pharmacology; D010455:Peptides / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D005755:Gastrins; D009842:Oligopeptides; D010455:Peptides; C060121:N-acetyl-gastrin releasing peptide (20-26) ethyl ester; D019886:Gastrin-Releasing Peptide; D001839:Bombesin; D002118:Calcium