Reduced peptide bond pseudopeptide analogues of secretin. A new class of secretin receptor antagonists.

The ability to assess the importance of secretin in various physiological processes is limited by the lack of specific potent antagonists. Recently, reduced peptide bond (psi) analogues of bombesin or substance P in which the -CONH- bond is replaced by -CH2NH- are reported to be receptor antagonists. To attempt to develop a new class of secretin receptor antagonists, we have adopted a similar strategy with secretin and sequentially altered the eight NH2-terminal peptide bonds, the biological active portion of secretin. In guinea pig pancreatic acini, secretin caused a 75-fold increase in cyclic AMP (cAMP). Secretin inhibited 125I-secretin binding with a half-maximal effect at 7 nM. Each of the psi analogues inhibited 125I-secretin binding. psi 4,5]Secretin was the most potent, causing the half-maximal inhibition at 4 microM, and was 2-fold more potent than the psi 1,2]secretin; 7-fold more than psi 3,4]secretin, psi 5,6]secretin, and psi 8,9]secretin; 9-fold more than psi 7,8]secretin; 13-fold more potent psi 6,7]secretin, and 17-fold more than psi 2,3]secretin. Secretin caused a half-maximal increase in cAMP at 1 nM. At concentrations up to 10 microM, psi 2,3]secretin, psi 4,5]secretin, and psi 8,9]secretin did not alter cAMP whereas psi 1,2]secretin and psi 6,7]secretin caused a detectable increase in cAMP at 10 nM, psi 7,8]secretin at 300 nM, psi 5,6]secretin at 1 microM, and psi 3,4]secretin at 10 microM. The psi 4,5], psi 2,3], and psi 8,9] analogues of secretin each inhibited 1 nM secretin-stimulated cAMP as well as psi 3,4]secretin, which functioned as a partial agonist. psi 4,5]Secretin was the most potent, causing half-maximal inhibition at 3 microM whereas psi 8,9]secretin was 6-fold less potent, and psi 2,3]secretin and psi 3,4]secretin were 17-fold less potent. psi 4,5]Secretin inhibited secretin-stimulated cAMP and binding of 125I-secretin in a competitive manner. psi 4,5]Secretin did not interact with cholecystokinin, bombesin, calcitonin gene-related peptide, or cholinergic receptors but did interact with receptors for vasoactive intestinal peptide, causing half-maximal inhibition at 72 microM and thus had a 18-fold higher affinity for secretin than vasoactive intestinal peptide receptors. These results indicate that reduced peptide bond analogues of the NH2 terminus of secretin represent a new class of secretin receptor antagonists. It is likely that in the future even more potent members of this class can be developed which may be useful to investigate the role of secretin in various physiological processes.