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

doi:10.1016/0024-3205(84)90009-2

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 journal › Article › peer-review

155 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 language	English (US)
Pages (from-to)	1371-1378
Number of pages	8
Journal	Life Sciences
Volume	34
Issue number	14
DOIs	https://doi.org/10.1016/0024-3205(84)90009-2
State	Published - 1984
Externally published	Yes

ASJC Scopus subject areas

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

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10.1016/0024-3205(84)90009-2

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Veber, D. F., Saperstein, R., Nutt, R. F., Freidinger, R. M., Brady, S. F., Curley, P., Perlow, D. S., Paleveda, W. J., Colton, C. D., Zacchei, A. G., Tocco, D. J., Hoff, D. R., Vandlen, R. L., Gerich, J. E., Hall, L., Mandarino, L., Cordes, E. H., Anderson, P. S., & Hirschmann, R. (1984). A super active cyclic hexapeptide analog of somatostatin. Life Sciences, 34(14), 1371-1378. https://doi.org/10.1016/0024-3205(84)90009-2

Veber, DF, Saperstein, R, Nutt, RF, Freidinger, RM, Brady, SF, Curley, P, Perlow, DS, Paleveda, WJ, Colton, CD, Zacchei, AG, Tocco, DJ, Hoff, DR, Vandlen, RL, Gerich, JE, Hall, L, Mandarino, L, Cordes, EH, Anderson, PS & Hirschmann, R 1984, 'A super active cyclic hexapeptide analog of somatostatin', Life Sciences, vol. 34, no. 14, pp. 1371-1378. https://doi.org/10.1016/0024-3205(84)90009-2

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title = "A super active cyclic hexapeptide analog of somatostatin",

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.",

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

year = "1984",

doi = "10.1016/0024-3205(84)90009-2",

language = "English (US)",

volume = "34",

pages = "1371--1378",

journal = "Life Sciences",

issn = "0024-3205",

publisher = "Elsevier Inc.",

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T1 - A super active cyclic hexapeptide analog of somatostatin

AU - Veber, Daniel F.

AU - Saperstein, Richard

AU - Nutt, Ruth F.

AU - Freidinger, Roger M.

AU - Brady, Stephen F.

AU - Curley, Paul

AU - Perlow, Debra S.

AU - Paleveda, William J.

AU - Colton, C. Dylion

AU - Zacchei, Anthony G.

AU - Tocco, Dominick J.

AU - Hoff, Dale R.

AU - Vandlen, Richard L.

AU - Gerich, John E.

AU - Hall, Larry

AU - Mandarino, Lawrence

AU - Cordes, Eugene H.

AU - Anderson, Paul S.

AU - Hirschmann, Ralph

PY - 1984

Y1 - 1984

N2 - 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.

AB - 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.

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SP - 1371

EP - 1378

JO - Life Sciences

JF - Life Sciences

IS - 14

ER -

A super active cyclic hexapeptide analog of somatostatin

Abstract

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