CYN 154806

Selective somatostatin sst(2) receptor blockade with the novel cyclic octapeptide, CYN-154806.[Pubmed:10818260]

Neuropharmacology. 2000 Jun 8;39(8):1443-50.

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.

Functional characterisation of the putative somatostatin sst2 receptor antagonist CYN 154806.[Pubmed:12616335]

Naunyn Schmiedebergs Arch Pharmacol. 2003 Jan;367(1):1-9.

The two forms (DTyr8 and LTyr8) of the putative somatostatin sst2 receptor antagonist CYN 154806 (Ac-4NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-D/LTyr-NH2) were investigated on recombinant human somatostatin receptors and endogenous guinea-pig ileum receptors. In radioligand binding studies using the agonist radioligands [125I]LTT-SRIF-28, [125I][Tyr10]cortistatin-14, [125I]CGP 23996 and [125I][Tyr3]octreotide in Chinese hamster lung fibroblast (CCL39) and Chinese hamster ovary (CHO) cells expressing human somatostatin receptors (hsst1-5), CYN 154806 binds to sst2 receptors with nanomolar affinity (pKD=8.14-8.89), 40- to 4500-fold higher than for sst1, sst3 or sst4. High affinity was also demonstrated for sst5 receptors, particularly for LTyr8CYN 154806 where the sst5 affinity was higher than for sst2 receptors when using [125I]CGP 23996 and [125I][Tyr3]octreotide. Functional properties of the compounds were examined in Chinese hamster ovary (CHO) cells expressing human sst2 receptors, in (1) inhibition of forskolin-stimulated adenylate cyclase, (2) stimulation of serum response element-driven luciferase expression and (3) [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTPS) binding. L- and DTyr8CYN 154806 showed full agonism at inhibition of forskolin-stimulated cAMP accumulation (pEC50=7.73 for both, Emax 104% and 78%, respectively), partial agonism at luciferase expression (pEC50=7.85 and 8.16, Emax=50% and 29%, respectively) and behaved as apparently silent antagonists at [35S]GTPS binding (no agonism observed, pKB=6.88 and 7.50, respectively). The agonist potential was confirmed in isolated guinea-pig ileum preparations via measurement of SRIF-induced inhibition of neurotransmission, where the L-isoform had marked agonism (pEC50=8.23, Emax=32%) whereas the D-isoform was apparently devoid of agonism. The present data suggest that CYN 154806 should be used with caution as an sst2 receptor antagonist tool, since it possesses intrinsic activity at sst2, and high affinity for both sst2 and sst5 receptors. The DTyr form, having lower intrinsic activity, especially in natural tissues, and greater selectivity for sst2 receptors, may be more reliable than LTyr CYN 154806.

Drug design at peptide receptors: somatostatin receptor ligands.[Pubmed:11931345]

J Mol Neurosci. 2002 Feb-Apr;18(1-2):15-27.

Somatostatin (SRIF, somatotropin release inhibiting factor), discovered for its inhibitory action on growth hormone (GH) secretion from pituitary, is an abundant neuropeptide. Two forms, SRIF14 and SRIF28 exist. Recently, a second family of peptides with very similar sequences and features was described; the cortistatins (CST), CST17 and CST29 which are brain selective. The five cloned SRIF receptors (sst1-5) belong to the G-protein coupled/ heptathelical receptor family. Structural and operational features distinguish two classes of receptors; SRIF1 - sst2/sst3/sst5 (high affinity for octreotide or seglitide) and SRIF2 = sst1/sst4(very low affinitty for the aforementioned ligands). The affinity of SRIF receptors for somatostatins and cortistatins is equally high, and it is not clear whether selective receptors do exist for one or the other of the peptides. Several radiologlands label all SRIF receptors, e.g., [125]LTT-SRIF28' [l25I]CGP23996, [125]Tyr10cortistatin or [125I]Tyr11SRIF14. In contrast, [125I]Tyr3octreotide, [125I]BIM23027, [125I]MK678 or [125I]D-Trp8SRIF14 label predominantly SRIF1 sites, especially sst2 and possibly sst5 receptors. In brain, [125I]Tyr3octreotide binding equates with sst2 receptor mRNA distribution. Native SRIF2receptors can be labeled with [125I]SRIF14 in the presence of high NaCl in brain (sst1) or lung (sst4) tissue. Short cyclic or linear peptide analogs show selectivity for sst2/sst5 (octreotide, lanreotide, BIM 23027), sst1 (CH-275), sst3 (sst3-ODN-8), or sst5 receptors (BIM 23268); although claims for selectivity have not always been confirmed. Beta peptides ith affinity for SRIF receptors are also reported. The general lack of SRIF receptor antagonists is unique for peptide receptors, although CYN 154806 is a selective and potent sst2 antagonist. Nonpeptide ligands are still rare, although a number of molecules have been reported with selectivity and potency for sst1 (L 757,519), sst2 (L 779,976), sst3 (L 796,778), sst4 (NNC 26-9100, L 803,087) or sst1/sst5 receptors (L 817,018). Such molecules are essential to establish the role of SRIF receptors, e.g., sst1 in hypothalamic glutamate currents: sst2 in inhibiting release of GH, glucagon, TSH, gastric acid secretion, pain, seizures and tumor growth, and sst5 in vascular remodeling and inhibition of insulin and GH release.

Identification and characterization of novel somatostatin antagonists.[Pubmed:8863814]

Mol Pharmacol. 1996 Oct;50(4):709-15.

The study of the five somatostatin receptor subtypes (SSTx, where x is the subtype number) has been hampered by the lack of high affinity antagonists. Potent and selective antagonists would increase our understanding of SST structure, function, and regulation. In this study, the identification of novel disulfide-linked cyclic octapeptide antagonists of somatostatin is described. The antagonists contain a core structure of a DL-cysteine pair at positions 2 and 7 of the peptides. Substitution of a D-cysteine at position 2 with an L-cysteine converts the full antagonist into a full agonist. All somatostatin receptor subtypes are coupled to inhibition of adenylate cyclase. The functional properties of these peptides have been determined in radioligand binding assays, in functional coupling of the SST2 subtype to yeast pheromone response pathway, and in cAMP accumulations. One peptide antagonist [Ac-4-NO2-Phe-c(D-Cys-Tyr-D-Trp-Lys-Thr-Cys)-D-Tyr-NH2] displays a binding affinity to SST2 comparable with that observed for the native hormone (Ki = 0.2 nM) and reverses somatostatin-mediated inhibition of cAMP accumulation in rat somatomammotroph GH4C1 cells, cells transfected with the SST2 and SST5 subtypes, as well as somatostatin-stimulated growth of yeast cells expressing the SST2 subtype. This class of somatostatin antagonists, which are the first to be described, should be useful for determination of somatostatin's diverse functions in vivo and in vitro.

CYN 154806, a cyclic octapeptide, is a potent and selective somatostatin sst2 receptor antagonist, with pIC50 values of 8.58, 5.41, 6.07, 5.76 and 6.48 for human recombinant sst2, sst1, sst3, sst4 and sst5 receptors respectively.

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