N-isobutyryl-His-Trp-Ala-Val-D-Ala-His-Leu-NHMe (ICI 216140) a potent in vivo antaconist analogue of bombesin/gastrin releasing peptide (BN/GRP) derived from the C-terminal sequence lacking the final methionine residue.
The GRP receptor mediated growth response in Swiss 3T3 cells has been used to identify BN/GRP antagonists. Analysis of bombesin antagonism by substance P analogues and by truncated GRP analogues revealed that deletion of the C-terminal methionine residue was important for antagonism. Des-Met analogues showing potent antagonist activity in the in vitro 3T3 system (IC50 approximately 2nM) were synthesized. Further structural modification of these peptides led to the identification of (CH3)2CHCO-His-Trp-Ala-Val-D-Ala-His-Leu-NHCH3 (ICI 216140) which reduced bombesin-stimulated rat pancreatic amylase secretion to basal levels when administered subcutaneously at 2.0 mg per kg.
Camble
R
R
ICI Pharmaceuticals, Alderley Park, Macclesfield, UK.
Cotton
R
R
Dutta
A S
AS
Garner
A
A
Hayward
C F
CF
Moore
V E
VE
Scholes
P B
PB
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D001839:Bombesin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D002478:Cells, Cultured; D019886:Gastrin-Releasing Peptide; D007202:Indicators and Reagents; D007700:Kinetics; D051379:Mice; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D010455:Peptides / Q000037:antagonists & inhibitors*; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007202:Indicators and Reagents; D009842:Oligopeptides; D010455:Peptides; D018004:Receptors, Bombesin; D017981:Receptors, Neurotransmitter; C061858:ICI 216140; D019886:Gastrin-Releasing Peptide; D001839:Bombesin