Synthesis and biological activity of highly potent octapeptide analogs of somatostatin

R. Z. Cai, B. Szoke, R. Lu, D. Fu, T. W. Redding, A. V. Schally

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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 D-Phe1, Ac-D-Phe1, or AcPhe1 followed by hexapeptide sequences Cys2-Phe3-D-Trp4-Lys5-Thr6-Cys7 or Cys2-Tyr3-D-Trp4-Lys5-Val6-Cys7 and Thr8-NH2 or Trp8-NH2 as C-terminal residues. D-Phe-(Cys-Tyr-D-Trp-Lys-Val-Cys)-Thr-NH2 and D-Phe-(Cys-Tyr-D-Trp-Lys-Val-Cys)-Trp-NH2 were 177 times and 113 time 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 that its L-Trp-4 diastereoisomer. The analogs D-Phe-(Cys-Tyr-D-Trp-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.

Original languageEnglish (US)
Pages (from-to)1896-1900
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Issue number6
StatePublished - 1986
Externally publishedYes

ASJC Scopus subject areas

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