Selective somatostatin sst(2) receptor blockade with the novel cyclic octapeptide, CYN-154806.
The cyclic octapeptide, CYN-154806, inhibited specific [(125)I]-[Tyr(11)]-SRIF binding to CHO-K1 cell membranes expressing human recombinant somatostatin (SRIF) sst(2) receptors (pIC(50) 8. 58) or rat sst(2(a)) and rat sst(2(b)) receptors (pIC(50) 8.35 and 8. 10, respectively). The affinity of CYN-154806 at other human somatostatin receptor types was at least 100 times lower (pIC(50) 5. 41-6.48). In functional studies, CYN-154806 inhibited SRIF-induced increases in extracellular acidification (EAR) in CHO-K1 cells expressing h sst(2) receptors (pK(B) 7.92) but had no effect on UTP-induced increases in EAR. CYN-154806 also blocked SRIF-induced increases [(35)S]-GTPgammaS binding in CHO-K1 cell membranes expressing h sst(2) receptors as well as rat sst(2(a)) and rat sst(2(b)) receptors (pK(B) 7.81, 7.68 and 7.96, respectively). In marked contrast, no blockade was observed at h sst(5) receptors in concentrations as high 10 microM. The antagonistic activity of CYN-154806 was also studied in isolated tissue preparations that are known to express endogenous SRIF receptors. Thus CYN-154806 blocked SRIF, but not DAMGO-induced inhibition of neurogenic contractions in rat isolated vas deferens and guinea-pig ileum (pK(B) 7.79 and 7.49, respectively). CYN-154806 had no effect on SRIF-28 induced inhibition of neurogenic contractions in guinea-pig vas deferens. The results demonstrate that CYN-154806 is a highly potent specific and selective SRIF sst(2) receptor blocking drug. Furthermore, sst(2) receptors mediate SRIF-induced inhibition of neurogenic contractions in rat vas deferens and guinea-pig ileum but not guinea-pig vas deferens which is thought to be mediated by sst(5) receptors.
Feniuk
W
W
Glaxo Institute of Applied Pharmacology, Department of Pharmacology, University of Cambridge, Tennis Court Road, CB2 1QJ, Cambridge, UK. wf2776@glaxowellcome.co.uk
Jarvie
E
E
Luo
J
J
Humphrey
P P
PP
D000701:Analgesics, Opioid / Q000494:pharmacology; D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D016466:CHO Cells; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D006224:Cricetinae; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000494:pharmacology; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006168:Guinea Pigs; D006801:Humans; D007082:Ileum / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009842:Oligopeptides / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017481:Receptors, Somatostatin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013004:Somatostatin / Q000378:metabolism / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
D000701:Analgesics, Opioid; C403089:CYN 154806; D009842:Oligopeptides; D017481:Receptors, Somatostatin; D011993:Recombinant Fusion Proteins; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D013004:Somatostatin; C093733:somatostatin receptor 2