Selective somatostatin sst(2) receptor blockade with the novel cyclic octapeptide, CYN-154806

The cyclic octapeptide, CYN-154806, inhibited specific [I-125]-[Tyr(11)]-SR IF binding to CHO-K1 cell membranes expressing human recombinant somatostat in (SRIF) sst(2) receptors (pIC(50) 8.58) or rat sst(2(a)) and rat set(2(b) ) receptors (pIC(50) 8.35 and 8.10, respectively). The affinity of CYN-1548 06 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-induc ed increases in extracellular acidification (EAR) in CHO-K1 cells expressin g h sst(2) receptors (pK(B) 7.92) but had no effect on UTP-induced increase s in EAR. CYN-153805 also blocked SRIF-induced increases [S-35]-GTP gamma S 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, respe ctively). In marked contrast, no blockade was observed at h sst(5) receptor s in concentrations as high 10 mu M. The antagonistic activity of CYN-15480 6 was also studied in isolated tissue preparations that are known to expres s endogenous SRIF receptors. Thus CYN-154806 blocked SRIF, but not DAMGO-in duced inhibition of neurogenic contractions in rat isolated vas deferens an d guinea-pig ileum (pK(B) 7.79 and 7.49, respectively). CYN-154806 had no e ffect on SRIF-28 induced inhibition of neurogenic contractions in guinea-pi g 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 whic h is thought to be mediated by sst(5) receptors. (C) 2000 Elsevier Science Ltd. All rights reserved.