Synthesis and biological activity of highly potent octapeptide analogs of somatostatin.
In the search for selective and long-acting analogs of somatostatin, nearly 200 compounds were synthesized by solid-phase methods, purified, and tested biologically. Among these octapeptides, some contained N-terminal (Formula: see text) were 177 times and 113 times more potent, respectively, than somatostatin in tests for inhibition of growth hormone release. These two octapeptides containing tyrosine and valine in positions 3 and 6, respectively, were more active and more selective than their Phe-3 and Thr-6 counterparts, D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Thr-NH2 and D-Phe-Cys-Phe-D-Trp-Lys-Thr-Cys-Trp-NH2. D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Thr-NH2 was also about 6 times more potent than its L-Trp-4 diastereoisomer. The analogs D-Phe-Cys-Tyr-Lys-Val-Cys-Thr-NH2 and D-Phe-Cys-Tyr-D-Trp-Lys-Val-Cys-Trp-NH2 showed a prolonged duration of action and were able to inhibit growth hormone release for at least 3 hr. Analogs of both Phe-3/Thr-6 and Tyr-3/Val-6 classes also suppressed the release of insulin and glucagon in rats and pentagastrin-induced secretion of gastric acid in dogs, but their potencies in these tests were much smaller than the growth-hormone-release inhibitory activity. Some of these analogs possessed antitumor activities as shown by the inhibition of growth of animal models of prostate, mammary, and ductal pancreatic tumors.
Cai
R Z
RZ
Szoke
B
B
Lu
R
R
Fu
D
D
Redding
T W
TW
Schally
A V
AV
D000595:Amino Acid Sequence; D000818:Animals; D004285:Dogs; D005744:Gastric Acid / Q000378:metabolism; D005753:Gastric Mucosa / Q000187:drug effects / Q000378:metabolism; D005934:Glucagon / Q000378:metabolism; D013006:Growth Hormone / Q000378:metabolism; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D012636:Secretory Rate / Q000187:drug effects; D013004:Somatostatin / Q000031:analogs & derivatives*
D007328:Insulin; D010455:Peptides; D013004:Somatostatin; D013006:Growth Hormone; D005934:Glucagon