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Research ArticleArticle

A Linear Hexapeptide Somatostatin Antagonist Blocks Somatostatin Activity In Vitro and Influences Growth Hormone Release in Rats

William R. Baumbach, Tikva A. Carrick, Mark H. Pausch, Brendan Bingham, Danielle Carmignac, Iain C. A. F. Robinson, Richard Houghten, C. Mark Eppler, Laura A. Price and John R. Zysk
Molecular Pharmacology November 1998, 54 (5) 864-873; DOI: https://doi.org/10.1124/mol.54.5.864
William R. Baumbach
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Tikva A. Carrick
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Mark H. Pausch
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Brendan Bingham
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Danielle Carmignac
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Iain C. A. F. Robinson
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Richard Houghten
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C. Mark Eppler
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Laura A. Price
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John R. Zysk
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Abstract

Somatostatin (SRIF) is the main inhibitory peptide regulating growth hormone (GH) secretion. It has been difficult to establish the role of endogenous SRIF release in the absence of pure SRIF antagonists. Although several SRIF antagonists have recently been described, none have been shown to possess in vivo activity in the absence of added SRIF. Here, an SRIF antagonist with no detectable agonist activity has been identified from a synthetic combinatorial hexapeptide library containing 6.4 × 107 unique peptides. Each peptide in the library is amino-terminally acetylated and carboxyl-terminally amidated and consists entirely ofd-amino acids. A SRIF-responsive yeast growth assay was used as a primary screening tool, and cAMP accumulation, competitive binding, and microphysiometry also were used to confirm and further characterize SRIF antagonist activity. The hexapeptide library was screened in stepwise iterative fashion to identify AC-178,335, a pure SRIF antagonist of the sequence Ac-hfirwf-NH2. Thisd-hexapeptide bound SRIF receptor type 2 with an affinity constant (K i) of 172 ± 12 nm, blocked SRIF inhibition of adenylate cyclase in vitro (IC50 = 5.1 ± 1.4 μm), and induced GH release when given alone (50 μg intravenously) to anesthetized rats with or without pretreatment with a long-acting SRIF agonist.

Footnotes

    • Received May 12, 1998.
    • Accepted July 28, 1998.
  • Send reprint requests to: Dr. William R. Baumbach, American Cyanamid, P.O. Box 400, Princeton, NJ 08543. E-mail:baumbachb{at}pt.cyanamid.com

  • ↵1 Current affiliation: CNS Disorders, Wyeth-Ayerst Research, CN 8000, Princeton, NJ 08543.

  • ↵2 Current affiliation: NovaScreen, 7170 Standard Dr., Hanover, MD 21076.

  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 54 (5)
Molecular Pharmacology
Vol. 54, Issue 5
1 Nov 1998
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Research ArticleArticle

A Linear Hexapeptide Somatostatin Antagonist Blocks Somatostatin Activity In Vitro and Influences Growth Hormone Release in Rats

William R. Baumbach, Tikva A. Carrick, Mark H. Pausch, Brendan Bingham, Danielle Carmignac, Iain C. A. F. Robinson, Richard Houghten, C. Mark Eppler, Laura A. Price and John R. Zysk
Molecular Pharmacology November 1, 1998, 54 (5) 864-873; DOI: https://doi.org/10.1124/mol.54.5.864

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Research ArticleArticle

A Linear Hexapeptide Somatostatin Antagonist Blocks Somatostatin Activity In Vitro and Influences Growth Hormone Release in Rats

William R. Baumbach, Tikva A. Carrick, Mark H. Pausch, Brendan Bingham, Danielle Carmignac, Iain C. A. F. Robinson, Richard Houghten, C. Mark Eppler, Laura A. Price and John R. Zysk
Molecular Pharmacology November 1, 1998, 54 (5) 864-873; DOI: https://doi.org/10.1124/mol.54.5.864
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