Four linear β2/β3-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 β2/β3-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.
- CCL39 cells
- Somatostatin (SRIF)
- Somatostatin receptor 4 (sst)
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