β23-di- and α/β3-tetrapeptide derivatives as potent agonists at somatostatin sst4 receptors

Caroline Nunn, Magnus Rueping, Daniel Langenegger, Edi Schuepbach, Thierry Kimmerlin, Peter Micuch, Konstanze Hurth, Dieter Seebach, Daniel Hoyer*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

48 Scopus citations

Abstract

Four linear β23-di- and α/β3-tetrapeptides (1-4) were investigated as somatostatin sst4 receptor agonists on recombinant human and mouse somatostatin receptors. Human somatostatin receptor subtypes 1-5 (sst1-5), and mouse somatostatin receptor subtypes 1,3,4 and 5, were characterised using the agonist radioligands [125I]LTT-SRIF-28, [125I][Tyr10]CST14 and [125I]CGP 23996 in stably transfected Chinese hamster lung fibroblast (CCL39) cells. The peptides bound selectively to sst4 receptors with nanomolar affinity (pKd=5.4-7.8). The peptides were investigated on second messenger systems both as agonists, and as antagonists to SRIF-14-mediated effects in CCL39 cells expressing mouse sst4 receptors, via measurement of inhibition of forskolin-stimulated adenylate cyclase activity, and stimulation of luciferase expression. The peptides showed full agonism or pronounced partial agonism (40 to 100% relative intrinsic activity) in both inhibition of forskolin-stimulated adenylate cyclase activity (pEC50=5.5-6.8), and luciferase expression (pEC50=5.5-6.5). The agonist potential was confirmed since antagonism was very difficult to establish. The data show that β23-di- and α/β3-tetrapeptide derivatives have agonist potential at recombinant somatostatin sst4 receptors. Therefore, they may be used to elucidate physiological and biochemical effects mediated by sst4, and may also have potential as therapeutic agents.

Original languageEnglish (US)
Pages (from-to)95-103
Number of pages9
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume367
Issue number2
DOIs
StatePublished - Feb 1 2003

Keywords

  • CCL39 cells
  • Luciferase
  • SRE
  • Somatostatin (SRIF)
  • Somatostatin receptor 4 (sst)
  • cAMP
  • β-peptide

ASJC Scopus subject areas

  • Pharmacology

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