Synthesis and biological activity of partially modified retro-inverso pseudopeptide derivatives of the C-terminal tetrapeptide of gastrin.
The effects of partial retro-inverso modifications of selected peptide bonds of the N-terminal tetrapeptide of gastrin have been studied. In some of the synthesized compounds, the phenylalanyl residue has been replaced by the (R,S)-2-benzylmalonyl, 3-phenylpropionyl, benzylcarbamoyl, or benzyloxycarbonyl moieties. All pseudopeptides showed affinity for the gastrin receptor, in vitro, with potencies varying from IC50 = 10(-7) to IC50 = 10(-4) M. These compounds exhibited little or no activity on acid secretion in the anesthetized rat but were able to antagonize the action of gastrin. Among the most potent were Boc-Trp-Leu-gAsp-CO-CH2CH2C6H5 (20) (ED50 = 0.15 microM/kg), Boc-Trp-Leu-gAsp-m(R,S)Phe-NH2 (3) (ED50 = 0.15 microM/kg), and Boc-Trp-gLeu-D-Asp-m(R,S)Phe-NH2 (7) (ED50 = 0.3 microM/kg).
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects; D005755:Gastrins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D011949:Receptors, Cholecystokinin / Q000187:drug effects / Q000378:metabolism; D013758:Tetragastrin / Q000138:chemical synthesis / Q000494:pharmacology*
D005755:Gastrins; D010446:Peptide Fragments; D011949:Receptors, Cholecystokinin; D013758:Tetragastrin