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 [H-3]thymidine incorporation into Swiss 3T3 cells (K-i = 7.8 +/- 2.0 and 0.5 +/- 0.1 nM, respectively).