Synthesis and biological evaluation of bombesin constrained analogues.
Analogues of bombesin which incorporate dipeptide or turn mimetics have been synthesized. One of them (compound 11) containing a seven-membered lactam ring revealed a good affinity for GRP/BN receptors on rat pancreatic acini (K(i) value of 1.7 +/- 0.4 nM) and on Swiss 3T3 cells (K(i) value of 1.0 +/- 0.2 nM). On the basis of this observation, antagonists containing the same dipeptide mimic were obtained by modification of the C-terminal part of the bombesin analogues. The most potent constrained compounds (15 and 17) were able to antagonize 1 nM bombesin-stimulated amylase secretion from rat pancreatic acini with high potency (K(i) = 21 +/- 3 and 3.3 +/- 1.0 nM, respectively) and 10(-7) M bombesin-stimulated ¿(3)Hthymidine incorporation into Swiss 3T3 cells (K(i) = 7.8 +/- 2. 0 and 0.5 +/- 0.1 nM, respectively).
Cristau
M
M
Laboratoire des Amino-acides, Peptides et Protéines and Centre de Biochimie Structurale, Faculté de Pharmacie, UMR 5810, CNRS-Universités Montpellier I & II, 15 avenue Charles Flahault, 34060 Montpellier, Cédex 2, France.
Devin
C
C
Oiry
C
C
Chaloin
O
O
Amblard
M
M
Bernad
N
N
Heitz
A
A
Fehrentz
J A
JA
Martinez
J
J
D016475:3T3 Cells; D000681:Amylases / Q000378:metabolism; D000818:Animals; D001839:Bombesin / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D018716:Molecular Mimicry; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D010179:Pancreas / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D018004:Receptors, Bombesin / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013936:Thymidine / Q000378:metabolism
D009842:Oligopeptides; D018004:Receptors, Bombesin; D000681:Amylases; D001839:Bombesin; D013936:Thymidine