TY - JOUR T1 - A Linear Hexapeptide Somatostatin Antagonist Blocks Somatostatin Activity <em>In Vitro</em> and Influences Growth Hormone Release in Rats JF - Molecular Pharmacology JO - Mol Pharmacol SP - 864 LP - 873 DO - 10.1124/mol.54.5.864 VL - 54 IS - 5 AU - William R. Baumbach AU - Tikva A. Carrick AU - Mark H. Pausch AU - Brendan Bingham AU - Danielle Carmignac AU - Iain C. A. F. Robinson AU - Richard Houghten AU - C. Mark Eppler AU - Laura A. Price AU - John R. Zysk Y1 - 1998/11/01 UR - http://molpharm.aspetjournals.org/content/54/5/864.abstract N2 - 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. ER -