A new peptidic somatostatin agonist with high affinity to all five somatostatin receptors.
All commercially available somatostatin analogs for clinical use have a preference for some but not all somatostatin receptor subtypes. We describe here the synthesis and evaluation in binding and cAMP assays with cell lines stably transfected with sst(1)-sst(5) of a new type of nonapeptide somatostatin analog with a reduced-sized and stabilized structure, Tyr(0)-(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe) (KE108). All five somatostatin receptors subtypes have an extremely high affinity for KE108, equivalent to SS-28 at sst(1) and two to four times higher than SS-28 at sst(2), sst(3), sst(4) and sst(5). Moreover, the compound has agonistic properties at all five subtypes, since it is able to inhibit the forskolin-stimulated cAMP production in sst(1)-sst(5) cells. It is stable for several hours in human serum. This analog may therefore represent a considerable improvement over commercially available somatostatin analogs as it will target all somatostatin receptor subtypes, a particular advantage for cancer-related applications, as human cancers can express concomitantly several somatostatin receptor subtypes.
Reubi
Jean Claude
JC
Division of Cell Biology and Experimental Cancer Research, Institute of Pathology, University of Berne, Switzerland. reubi@pathology.unibe.ch
Eisenwiener
Klaus-Peter
KP
Rink
Hans
H
Waser
Beatrice
B
Mäcke
Helmut R
HR
D000595:Amino Acid Sequence; D000818:Animals; D001667:Binding, Competitive; D016466:CHO Cells; D002460:Cell Line; D005576:Colforsin / Q000494:pharmacology; D006224:Cricetinae; D000242:Cyclic AMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006801:Humans; D009842:Oligopeptides / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D020033:Protein Isoforms / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D017481:Receptors, Somatostatin / Q000819:agonists* / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection
D009842:Oligopeptides; D010456:Peptides, Cyclic; D020033:Protein Isoforms; D017481:Receptors, Somatostatin; C473958:Tyr(0)-(cyclo-D-Dab-Arg-Phe-Phe-D-Trp-Lys-Thr-Phe); D005576:Colforsin; D013004:Somatostatin; D000242:Cyclic AMP