Beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptide derivatives as potent agonists at somatostatin sst(4) receptors.
Four linear beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptides (1-4) were investigated as somatostatin sst(4) receptor agonists on recombinant human and mouse somatostatin receptors. Human somatostatin receptor subtypes 1-5 (sst(1-5)), and mouse somatostatin receptor subtypes 1,3,4 and 5, were characterised using the agonist radioligands [(125)I]LTT-SRIF-28, [(125)I][Tyr(10)]CST(14) and [(125)I]CGP 23996 in stably transfected Chinese hamster lung fibroblast (CCL39) cells. The peptides bound selectively to sst(4) receptors with nanomolar affinity (pK(d)=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 sst(4 )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 (pEC(50)=5.5-6.8), and luciferase expression (pEC(50)=5.5-6.5). The agonist potential was confirmed since antagonism was very difficult to establish. The data show that beta(2)/beta(3)-di- and alpha/beta(3)-tetrapeptide derivatives have agonist potential at recombinant somatostatin sst(4) receptors. Therefore, they may be used to elucidate physiological and biochemical effects mediated by sst(4), and may also have potential as therapeutic agents.
Nunn
Caroline
C
Nervous System Research, WSJ 386/745, Novartis Pharma AG, 4002, Basel, Switzerland.
Rueping
Magnus
M
Langenegger
Daniel
D
Schuepbach
Edi
E
Kimmerlin
Thierry
T
Micuch
Peter
P
Hurth
Konstanze
K
Seebach
Dieter
D
Hoyer
Daniel
D
D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D003412:Cricetulus; D004151:Dipeptides / Q000138:chemical synthesis / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008024:Ligands; D008156:Luciferases / Q000096:biosynthesis; D008168:Lung / Q000166:cytology; D008565:Membrane Proteins; D051379:Mice; D009842:Oligopeptides / Q000138:chemical synthesis / Q000494:pharmacology*; D011869:Radioligand Assay; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000378:metabolism; D013329:Structure-Activity Relationship
D004151:Dipeptides; D004791:Enzyme Inhibitors; D008024:Ligands; D008565:Membrane Proteins; D009842:Oligopeptides; D017481:Receptors, Somatostatin; C098681:somatostatin receptor subtype-4; D005576:Colforsin; D008156:Luciferases; D000262:Adenylyl Cyclases