A super active cyclic hexapeptide analog of somatostatin

Daniel F. Veber, Richard Saperstein, Ruth F. Nutt, Roger M. Freidinger, Stephen F. Brady, Paul Curley, Debra S. Perlow, William J. Paleveda, C. Dylion Colton, Anthony G. Zacchei, Dominick J. Tocco, Dale R. Hoff, Richard L. Vandlen, John E. Gerich, Larry Hall, Lawrence Mandarino, Eugene H. Cordes, Paul S. Anderson, Ralph Hirschmann

Research output: Contribution to journalArticlepeer-review

144 Scopus citations

Abstract

The cyclic hexapeptide, cyclo (Pro-Phe-D-Trp-Lys-Thr-Phe), I, has been shown to have the biological properties of somatostatin. We now report structure-activity studies which optimize the potency of this cyclic hexapeptide series with the synthesis of cyclo (N-Me-Ala-Tyr-D-Trp-Lys-Val-Phe), II, which is 50-100 times more potent than somatostatin for the inhibition of insulin, glucagon and growth hormone release. The hydroxyl group of tyrosine is seen to lend a 10-fold enhancement to the potency. Potency also is found to be correlated with hydrophobicity. II is found to improve the control of postprandial hyperglycemia in diabetic animals when given in combination with insulin. The analog is found to be quite stable in the blood and in the gastrointestinal tract, but the bioavailability after oral administration is only 1-3%. The biological properties and long duration of II should allow clinical evaluation of the inhibition of glucagon release as an adjunct to insulin in the treatment of patients with diabetes.

Original languageEnglish (US)
Pages (from-to)1371-1378
Number of pages8
JournalLife Sciences
Volume34
Issue number14
DOIs
StatePublished - 1984
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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