Cyclic hexa- and pentapeptide somatostatin analogues with reduced gastric inhibitory activity.
The gastric inhibitory activity of cyclic hexa- and pentapeptide analogues of somatostatin was investigated in conscious cats with gastric fistulae. Gastric acid and pepsin secretions were stimulated by pentagastrin. Cyclo(Phe-Phe-D-Trp-Lys-Thr-Phe) showed no inhibition of acid secretion at molar doses up to 50-times the ID50 for somatostatin. This peptide inhibited pepsin secretion at the highest dose (50 micrograms kg-1 hr-1), and its potency is approximately 0.005 compared with somatostatin (1.0). Cyclo(Pro-Phe-D-Trp-Lys-Thr-Phe) inhibited acid (approximately 50%) and pepsin (approximately 85%) secretions, but the inhibition was not dose-related being similar with doses of 10 to 50 micrograms kg-1 hr-1. The cyclic pentapeptide, cyclo(7-aminoheptanoyl-Phe-D-Trp-Lys-Thr), was inactive in the dose range studied, with a potency less than 0.01. Cyclo[7-aminoheptanoyl-Phe-D-Trp-Lys-Thr(Bzl)] has been described as a somatostatin antagonist with respect to inhibition of growth hormone, insulin and glucagon release in rats [2]. Up to 60-fold molar excesses of this peptide failed to antagonise the inhibitory activity of somatostatin in the stomach. The results demonstrate that residues outside the central 6-11 region of somatostatin are very important for its gastric activity. The lack of gastric antagonistic activity of the pentapeptide antagonist indicates that these residues are likely to be involved in receptor recognition/binding.
D000818:Animals; D002415:Cats; D004305:Dose-Response Relationship, Drug; D005744:Gastric Acid / Q000378:metabolism*; D010418:Pentagastrin / Q000494:pharmacology; D010434:Pepsin A / Q000378:metabolism*; D010446:Peptide Fragments / Q000494:pharmacology; D013004:Somatostatin / Q000031:analogs & derivatives* / Q000494:pharmacology
D010446:Peptide Fragments; C036876:cyclo(7-aminoheptanoyl-phenylalanyl-tryptophyl-lysyl-threonyl); C040704:cyclo(Pro-Phe-Trp-Lys-Thr-Phe); D013004:Somatostatin; C043819:somatostatin, cyclic hexapeptide(Phe-Phe-Trp-Lys-Thr-Phe)-; C043820:cyclo(7-aminoheptanoylphenylalanyl-tryptophyl-lysyl-benzylthreonyl); D010434:Pepsin A; D010418:Pentagastrin