title: Biological effects and receptor binding affinities of new pseudononapeptide bombesin/GRP receptor antagonists with N-terminal D-Trp or D-Tpi.
abstract: In an attempt to produce more powerful (effective) bombesin/GRP receptor antagonists, the D forms of Trp or Trp analog (Tpi) were introduced at position 6 in two pseudononapeptides, Leu13 psi (CH2NH)Leu14-bombesin(6-14) and Leu13 psi(CH2NH)Phe14-bombesin (6-14). These antagonists were tested for their ability to inhibit basal and gastrin releasing peptide (GRP) (14-27)-induced amylase release from rat pancreatic acini in a superfusion assay. They were also assessed for the inhibition of 125I-Tyr4-bombesin binding to Swiss 3T3 and small cell lung carcinoma cell line H-345 and the mitogenic response of Swiss 3T3 cells induced by GRP(14-27). The peptides, when given alone, did not stimulate amylase secretion, but were able to inhibit gastrin releasing peptide (14-27)-induced amylase release. All of the antagonists showed strong binding affinities for Swiss 3T3 and H-345 cells and suppressed the GRP(14-27)-induced increase of [3H]thymidine incorporation into DNA of Swiss 3T3 cells at nanomolar concentrations. Antagonist D-Tpi6,Leu13 psi (CH2NH)Leu14-bombesin (6-14)(RC-3095) was slightly more potent in these assays than D-Trp6,Leu13 psi (CH2NH)Leu14-bombesin (6-14)(RC-3125). Nevertheless, D-Trp6,Leu13 psi (CH2NH)Phe14-bombesin (6-14) showed the highest binding affinity for Swiss 3T3 and H345 cells and it was the most potent inhibitor of GRP(14-27)-induced amylase secretion. This antagonist RC-3420 was particularly effective in inhibiting the growth of Swiss 3T3 cells, exhibiting an IC50 value less than 1 nM.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Endocrine, Polypeptide and Cancer Institute, Veterans Administration Medical Center, New Orleans, Louisiana.
authors.forename: S
authors.initials: S
authors.lastname: Radulovic
authors.forename: R Z
authors.initials: RZ
authors.lastname: Cai
authors.forename: P
authors.initials: P
authors.lastname: Serfozo
authors.forename: K
authors.initials: K
authors.lastname: Groot
authors.forename: T W
authors.initials: TW
authors.lastname: Redding
authors.forename: J
authors.initials: J
authors.lastname: Pinski
authors.forename: A V
authors.initials: AV
authors.lastname: Schally
mesh_terms: D016475:3T3 Cells; D000595:Amino Acid Sequence; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D010179:Pancreas / Q000187:drug effects / Q000201:enzymology; D051381:Rats; D011919:Rats, Inbred Strains; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship
chemical_list: D009842:Oligopeptides; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; D000681:Amylases; D001839:Bombesin