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

Abstract

The cyclic octapeptide, CYN-154806, inhibited specific [ 125I]-[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 [ 35S]-GTPγS 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 μM. 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.