Opportunities in somatostatin research: biological, chemical and therapeutic aspects

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Weckbecker, G., Lewis, I., Briner, U. & Bruns, C. SOM230, A new somatostatin peptidomimetic with unique binding and endocrine profile. Proc. 5th Eur. Congr. Endocrinol. Turin, Italy (June, 2001).

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Weckbecker, G., Briner, U., Lewis, I. & Bruns, C. SOM230: a new somatostatin peptidomimetic with potent inhibitory effects on the growth hormone/insulin-like growth factor-I axis in rats, primates, and dogs. Endocrinology 143, 4123–4130 (2002).

Bruns, C., Lewis, I., Briner, U., Meno-Tetang, G. & Weckbecker, G. SOM230: a novel somatostatin peptidomimetic with a broad somatotropin release inhibiting factor (SRIF) receptor binding and a unique antisecretory profile. Eur. J. Endocrinol. 146, 707–716 (2002).

Lewis, I. et al. A novel somatostatin mimic with broad somatotropin release inhibitory factor receptor binding and superior therapeutic potential. J. Med. Chem. 46, 2334–2344 (2003). References 24–29 describe the in vivo studies, binding and functional studies, and the synthesis and medicinal chemistry of SOM230.

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Hoyer, D. et al. in The IUPHAR Compendium of Receptor Characterisation and Classification (IUPHAR Committee on Receptor Nomenclature and Drug Classification) 354–356 (IUPHAR Media, London, 2000). This section of the compendium presents the IUPHAR-based SRIF receptor nomenclature.

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Cejvan, K., Coy, D. H. & Efendic, S. Intra-islet somatostatin regulates glucagon release via type 2 somatostatin receptors in rats. Diabetes 52, 1176–1181 (2003).

Barkan, A. L. et al. Ghrelin secretion in humans is sexually dimorphic, suppressed by somatostatin, and not affected by the ambient growth hormone levels. J. Clin. Endocrinol. Metab. 88, 2180–2184 (2003).

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Dimaraki, E. V., Jaffe, C. A., Bowers, C. Y., Marbach, P. & Barkan, A. L. Pulsatile and nocturnal growth hormone secretions in men do not require periodic declines of somatostatin. Am. J. Physiol. Endocrinol. Metabol. 285, C1205–C1204 (2003).

Gong, A. Y. et al. Somatostatin stimulates ductal bile absorption and inhibits ductal bile secretion in mice via SSTR2 on cholangiocytes. Am. J. Physiol. Cell Physiol. 284, 1205–1214 (2003).

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Weckbecker, G., Raulf, F., Tolcsvai, L. & Bruns, C. Potentiation of the antiproliferative effects of anticancer drugs by octreotide in vitro and in vivo. Digestion 57, 22–28 (1996).

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Weckbecker, G., Stolz, B., Susini, C. & Bruns, C. in Octreotide: the Next Decade (ed. Lamberts, S. W. J.) 339–352 (BioScientifica, Bristol, 1999).

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Florio, T. et al. Somatostatin inhibits tumor angiogenesis and growth via somatostatin receptor-3-mediated regulation of endothelial nitric oxide synthase and mitogen-activated protein kinase activities. Endocrinology 144, 1574–1584 (2003).

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Srikant, C. B. & Shen, S. H. Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast cancer adenocarcinoma cells. Endocrinology 137, 3461–3468 (1996).

Florio, T. et al. The activation of the phosphotyrosine phosphatase-η (r-PTPη) is responsible for the somatostatin inhibition of PC CI3 thyroid cell proliferation. Mol. Endocrinol. 15, 1838–1852 (2001).

Hortala, M. et al. Inhibitory role of the somatostatin receptor SST2 on the intracrine-regulated cell proliferation induced by the 210-amino acid fibroblast growth factor-2 isoform: implication of JAK2. J. Biol. Chem. 278, 20574–20581 (2003).

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Weckbecker, G., Raulf, F., Bodmer, D. & Bruns, C. Indirect antiproliferative effect of the somatostatin analog octreotide on MIA PaCa-2 human pancreatic carcinoma in nude mice. Yale J. Biol. Med. 70, 549–554 (1997).

Weckbecker, G., Tolcsvai, L., Stolz, B., Pollak, M. & Bruns, C. Somatostatin analog octreotide enhances the antineoplastic effects of tamoxifen and ovariectomy on 7,12-dimethylbenz(a)anthracene-induced rat mammary carcinomas. Cancer Res. 54, 6334–6337 (1994).

Sun, Q. -Q., Huguenard, J. R. & Prince D. A. Somatostatin inhibits thalamic network oscillations in vitro: actions on the GABAergic neurons of the reticular nucleus. J. Neurosci. 22, 5374–5386 (2002).

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Hofland, L. J. & Lamberts, S. W. J. The pathophysiological consequences of somatostatin receptor internalization and resistance. Endocrine Rev. 24, 28–47 (2003). Comprehensive review on SRIF receptor internalization.

Reubi, J. C., Waser, B., Schaer, J. -C. & Laissue, J. A. Somatostatin receptor sst1–sst5 expression in normal and neoplastic human tissues using receptor autoradiography with subtype-selective ligands. Eur. J. Nucl. Med. Mol. Imaging 28, 836–846 (2001).

Kulaksiz, H. et al. Identification of somatostatin receptor subtypes 1,2A, 3, and 5 in neuroendocrine tumors with subtype specific antibodies. Gut 50, 52–60 (2002).

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Csaba, Z., Bernard, V., Helboe, L., Bluet-Pajot, M. T. & Bloch, B. In vivo internalization of the somatostatin sst2A receptor in rat brain: evidence for translocation of cell-surface receptors into the endosomal recycling pathway. Mol. Cell. Neuroscience 17, 646–661 (2001).

Krenning, E. P. et al. Somatostatin receptor scintigraphy with [111In-DTPA-D-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients. Eur. J. Nucl. Med. 20, 716–731 (1993). The first major clinical experience with SRIF receptor scintigraphy.

De Jong, M. et al. Internalization of radiolabelled [DTPA0]octreotide and [DOTA0,Tyr3]octreotide: peptides for somatostatin receptor–targeted scintigraphy and radionuclide therapy. Nucl. Med. Commun. 19, 283–288 (1998).

Schally, A. V. & Nagy A. Cancer chemotherapy based on targeting of cytotoxic peptide conjugates to their receptors on tumors. Eur. J. Endocrinol. 141, 1–14 (1999).

Froidevaux, S. et al. Differential regulation of somatostatin receptor type 2 (sst 2) expression in AR4-2J tumor cells implanted into mice during octreotide treatment. Cancer Res. 59, 3652–3657 (1999).

Arnold, R., Simon, B. & Wied, M. Treatment of neuroendocrine GEP tumours with somatostatin analogues: a review. Digestion 62, 84–91 (2000).

George, S. R., O'Dowd, B. F. & Lee, S. P. G-protein-coupled receptor oligomerization and its potential for drug discovery. Nature Rev. Drug Discov. 2, 808–820 (2002).

Rocheville, M. et al. Receptors for dopamine and somatostatin: formation of hetero-oligomers with enhanced functional activity. Science 288, 154–157 (2000). Describes the hetero-oligomerization of SRIF receptors.

Rocheville, M. et al. Subtypes of the somatostatin receptor assemble as functional homo- and heterodimers J. Biol. Chem. 275, 7862–7869 (2000).

Pfeiffer, M. et al. Homo- and heterodimerization of somatostatin receptor subtypes. Inactivation of sst(3) receptor function by heterodimerization with sst(2A). J. Biol. Chem. 276, 14027–14036 (2001).

Pfeiffer, M. et al. Heterodimerization of somatostatin and opioid receptors cross-modulates phosphorylation, internalization, and desensitization. J. Biol. Chem. 277, 19762–19772 (2002).

Selmer, I. -S., Schindler, M., Allen, J. P., Humphrey, P. P. A. & Emson, P. C. Advances in understanding neuronal somatostatin receptors. Regul. Pept. 90, 1–18 (2000).

Murphy, W. A., Lance, V. A., Moreau, S., Moreau, J. & Coy, D. H. Inhibition of rat prostate tumor growth by an octapeptide analog of somatostatin. Life Sci. 40, 2515–2522 (1987).

Caron, P., Morange-Ramos, I., Cogne, M. & Jaquet, P. Three year follow-up of acromegalic patients treated with intramuscular slow-release lanreotide. J. Clin. Endocrinol. Metab. 82, 18–22 (1997).

Veber, D. F. et al. A potent cyclic hexapeptide analogue of somatostatin. Nature 292, 55–58 (1981). Reports a SRIF analogue structure with further reduced size.

Van der Hoek, J. et al. A single dose comparison of the acute effects between the new somatostatin analog SOM230 and octreotide in acromegalic patients. J. Clin. Endocrinol. Metab. 88 (in the press). Demonstration of efficacy of SOM230 in acromegalic patients.

Raynor, K. et al. Cloned somatostatin receptors: identification of subtype-selective peptides and demonstration of high affinity binding of linear peptides. Mol. Pharmacol. 43, 838–844 (1993).

Shimon, I. et al. Somatostatin receptor subtype specificity in human fetal pituitary cultures, differential role of SSTR2 and SSTR5 for growth hormone, thyroid-stimulating hormone, and prolactin regulation. J. Clin. Invest. 99, 789–798 (1997). Describes the role of sst 5 in controlling growth hormone release.

Reubi, J. C., Eisenwiener, K. -P., Rink, H., Waser, B. & Mäcke, H. R. A new peptidic somatostatin agonist with high affinity to all five somatostatin receptors. Eur. J. Pharmacol. 456, 45–49 (2002). Report on a novel universal SRIF receptor ligand.

Rivier, J. E. et al. Potent somatostatin undecapeptide agonists selective for somatostatin receptor 1 (sst1). J. Med. Chem. 44, 2238–2246 (2001).

Rajeswaran, W. G., Hocart, S. J., Murphy, W. A., Taylor, J. E. & Coy, D. H. N-methyl scan of somatostatin octapeptide agonists produces interesting effects on receptor subtype specificity. J. Med. Chem. 44, 1416–1421 (2001).

Afargan, M. et al. Novel long-acting somatostatin analog with endocrine selectivity: potent suppression of growth hormone but not of insulin. Endocrinology 142, 477–486 (2001). Reports the discovery of PTR3173.

Gazal, S. et al. Human somatostatin receptor specificity of backbone-cyclic analogues containing novel sulfur building units. J. Med. Chem. 45, 1665–1671 (2002).

Gademann, K., Kimmerlin, T., Hoyer, D. & Seebach, D. Peptide folding induces high and selective affinity of a linear and small β-peptide to the human somatostatin receptor 4. J. Med. Chem. 44, 2460–2468 (2001). Describes the discovery of a β-peptide SRIF analogue.

Nunn, C. et al. β2/β3- and α/β3-tetrapeptide derivatives as potent agonists at somatostatin sst4 receptors. Naunyn Schmiedeberg's Arch. Pharmacol. 367, 95–103 (2003).

Seebach, D., Schaeffer, L., Brenner, M. & Hoyer, D. Design and synthesis of γ-dipeptide derivatives with submicromolar affinities for human somatostatin receptors. Angew. Chem. Int. Ed. Engl. 42, 776–778 (2003). Reports the discovery of γ-dipeptide SRIF mimics.

Bass, R. T. et al. Identification and characterization of novel somatostatin antagonists. Mol. Pharmacol. 50, 709–715 (1996). First SRIF peptide antagonist published.

Feniuk, W., Jarvie, E., Luo, J. & Humphrey, P. P. A. Selective somatostatin sst2 receptor blockade with the novel cyclic octapeptide, CYN-154806. Neuropharmacology 39, 1443–1450 (2000).

Hocart, S. J., Jain, R., Murphy, W. A., Taylor, J. E. & Coy, D. H. Highly potent cyclic disulfide antagonists of somatostatin. J. Med. Chem. 42, 1863–1871 (1999).

Reubi, J. C. et al. SST3-selective potent peptidic somatostatin receptor antagonists. Proc. Natl Acad. Sci. USA 97, 13973–13978 (2000).

Keri, G. et al. Novel somatostatin analogs with tyrosine kinase inhibitory and antitumor activity. Biochem. Biophys. Res. Commun. 191, 681–687 (1993).

Pinter, E. et al. Pharmacological characterization of the somatostatin analogue TT-232: effects on neurogenic and non-neurogenic inflammation and neuropathic hyperalgesia. Naunyn Schmiedebergs Arch. Pharmacol. 366, 142–150 (2002).

Li, H., Jiang, X., Howell, S. B. & Goodman, M. Synthesis, conformational analysis and bioactivity of Lan-7, a lanthionine analog of TT-232. J. Pept. Sci. 6, 26–35 (2000).

Yang, L. Non-peptide somatostatin receptor ligands. Ann. Rep. Med. Chem. 34, 209–218 (1999).

Rohrer, S. P. & Schaeffer, J. M. Identification and characterization of subtype selective somatostatin receptor agonists. J. Physiol. 94, 211–215 (2000).

Pasternak, A. et al. Potent, orally bioavailable somatostatin agonists: good absorption achieved by urea backbone cyclization. Bioorg. Med. Chem. Lett. 9, 491–496 (1999). This paper describes orally available SRIF mimetics.

Hirschmann, R. et al. Nonpeptidal peptidomimetics with β-D-glucose scaffolding. A partial somatostatin agonist bearing a close structural relationship to a potent, selective substance P antagonist. J. Am. Chem. Soc. 114, 9217–9218 (1992). Early work on non-peptide SRIF analogues.

Hirschmann, R. et al. Modulation of receptor and receptor subtype affinities using diastereomeric and enantiomeric monosaccharide scaffolds as a means to structural and biological diversity. A new route to ether synthesis. J. Med. Chem. 41, 1382–1391 (1998).

Prasad, V. et al. Effects of heterocyclic aromatic substituents on binding affinities at two distinct sites of somatostatin receptors. Correlation with the electrostatic potential of the substituents. J. Med. Chem. 46, 1858–1869 (2003).

Ankersen, M. et al. Discovery of a novel non-peptide somatostatin agonist with SST4 selectivity. J. Am. Chem. Soc. 120, 1368–1373 (1998). Discovery of a selective non-peptide SRIF agonist.

Souers, A. J. et al. Optimization of a somatostatin mimetic via constrained amino acid and backbone incorporation. Bioorg. Med. Chem. Lett. 10, 2731–2733 (2000). Discovery of a thioether SRIF mimic.

Hoyer, D. et al. NVP-SRA880, a somatostatin sst1 receptor antagonist promotes social interactions, reduces aggressive behaviour and stimulates learning. The Pharmacologist 44 (Suppl. 1), A254 (2002). First SRIF antagonist tested in clinical trials.

Poitout, L. et al. Identification of potent non-peptide somatostatin antagonists with sst3 selectivity. J. Med. Chem. 44, 2990–3000 (2001).

Bakker, W. H. et al. [111In-DTPA-D-Phe1]-octreotide, a potential radiopharmaceutical for imaging of somatostatin receptor-positive tumors: synthesis, radiolabeling and in vitro validation. Life Sci. 49, 1583–1591 (1991). Discovery of radiolabelled octreotide.

Stolz, B. et al. The somatostatin receptor-targeted radiotherapeutic [90Y-DOTA-D-Phe1, Tyr3](octreotide (90Y-SMT 487) eradicates experimental rat pancreatic CA 20948 tumours. Eur. J. Nucl. Med. 25, 668–674 (1998). Discovery of the first SRIF analogue radiotherapeutic, SMT487, which is presently being tested clinically.

Virgolini, I. et al. Experience with indium-111 and yttrium-90-labeled somatostatin analogs. Curr. Pharm. Des. 8, 1781–1807 (2002). A comprehensive review of radiolabelled SRIF analogues.

De Jong, M. et al. Somatostatin receptor-targeted radiotherapy of tumors: preclinical and clinical findings. Sem. Nucl. Med. 32, 133–140 (2002).

Reubi, J. C. et al. Affinity profiles for human somatostatin receptor subtypes SST1-SST5 of somatostatin radiotracers selected for scintigraphic and radiotherapeutic use. Eur. J. Nuc. Med. 27, 273–282 (2000).

Jamar, F. et al. 86Y-DOTA0-D-Phe1-Tyr3-octreotide (SMT487) a phase 1 clinical study: pharmacokinetics, biodistribution and renal protective effect of different regimens of amino acid co-infusion. Eur. J. Nucl. Med. Mol. Imaging 30, 510–518 (2003).

Bolli, G. B., Gottesman, I. S. & Gerich, J. E. Preliminary experience on treatment of insulin-dependent diabetes mellitus with a long-acting somatostatin analogue (L363,586). Hormone Res. 29, 95–98 (1988).

Gerich, J. E. Lorenzi, M., Schneider, V. & Forsham, P. H. Effect of somatostatin on plasma glucose and insulin responses to glucagon and tolbutamide in man. J. Clin. Endocrinol. Metab. 39, 1057–1060 (1974).

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