Somatostatin analogs

Janecka, Anna; Zubrzycka, Maria; Janecki, Tomasz

doi:10.1034/j.1399-3011.2001.00873.x

Cited by 88 publications

(100 citation statements)

References 106 publications

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“…5 The successful use of radiolabelled somatostatin for imaging and radionuclide therapy has prompted the development of new cyclic and acyclic analogues with better receptor affinity and higher stability under physiological conditions. 6 Octreotide, 7 1 (Chart 1), a metabolically-stabilized cycloctapeptide analogue of somatostatin that includes D-amino acids to enhance resistance to enzymatic degradation and a cystine bridge to stabilize the pharmacophore β-turn, is particularly interesting because of its high affinity and selectivity for the receptor sst 2 octreotide which are used in the clinics for molecular imaging and therapy of neuroendocrine tumors, respectively. 8 Octreotide has also been conjugated to cytotoxic organic compounds such as doxorubicin, camptothecin and paclitaxel, with promising results in some cases because of the reduced toxicity and the increased selectivity of the conjugates compared with that of the free drug.…”

Section: Introductionmentioning

confidence: 99%

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

Barragán¹,

Carrión-Salip

Gómez‐Pinto

et al. 2012

Bioconjugate Chem.

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Conjugateswith an active participation of somatostatin receptors in cellular uptake. Similar cytotoxic activity was found in a normal cell line (IC 50 = 45 + 2.6 µM in CHO cells), which can be attributed to a similar level of expression of somatostatin subtype-2 receptor. These studies provide new insights into the effect of receptor-binding peptide conjugation on the activity of metal-based anticancer drugs, and demonstrate the potential of such hybrid compounds to target tumor cells specifically.

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Section: Introductionmentioning

confidence: 99%

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

Barragán¹,

Carrión-Salip

Gómez‐Pinto

et al. 2012

Bioconjugate Chem.

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“…Similarly, the disulfide bridge in U-II would act in a similar manner. Structure-activity relationship (SAR) studies of SST already showed that these pharmacophoric features are essential for the SST biological activity (Janecka et al, 2001). Furthermore, previous fish U-II (Itoh et al, 1987) and human U-II (Kinney et al, 2001(Kinney et al, , 2002Flohr et al, 2002) SAR studies showed that the highly conserved C-terminal segment CF-WKYCV is the minimal sequence required to maintain a high potency and that Lys-8 appeared as an important residue for U-II activity (Carmada et al, 2002).…”

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confidence: 99%

Functional and Binding Characterizations of Urotensin II-Related Peptides in Human and Rat Urotensin II-Receptor Assay

Brkovic¹,

Hattenberger²,

Kostenis³

et al. 2003

J Pharmacol Exp Ther

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Urotensin II (U-II; cyclo [5][6][7][8][9][10] [H-Glu-Thr-Pro-Asp-Cys-Phe-TrpLys-Tyr-Cys-Val-OH]) is a potent vasoconstrictor in mammals, and it is postulated that it plays a central role in cardiovascular homeostasis. Thus, we initiated a structure-to-function analysis of this peptide characterized by a N-terminal tail and a cyclic core formed through a disulfide bridging. A total of 41 analogs focusing on these characteristics were developed and evaluated using a binding assay on membranes from a stable HEK-293 cell line containing the human or rat U-II receptor, a functional assay for Ca 2ϩ mobilization on transiently transfected CHO-K1 cells with the human or rat U-II receptor, and a rat thoracic aorta bioassay. At first, the focus was applied on peptide compounds containing exocyclic modifications. From this series, it appeared that only valine-11 played a significant role although it is not an essential amino acid. Similarly, endocyclic and ring transformations of hU-II were also studied. In most cases, a detrimental effect on affinity and biological activity was observed. However, two compounds, [Tyr 6 ]hU-II and [Phe 9 ]hU-II, retained affinity and activity. So far, our binding, functional, and pharmacological data clearly demonstrated the minor contribution of the N-terminal segment and the essential role of the cyclic structure. More particularly, three residues within the loop, i.e., Trp-7, Lys-8, and Tyr-9, are required for receptor recognition and activation. This three-pole feature, kept by the disulfide bond in a correct spatial arrangement, appears as the key pharmacophore for the U-II receptor.

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“…Such ''hits'' have not been easy to find for the galanin receptors (9), and the two low-affinity compounds that were found were not chemically tractable. Although most neuropeptide-receptor ligands that have reached clinical use are antagonists (32), some neuropeptide-receptor agonists have been developed from peptidomimetics, most often for cyclic peptide ligands such as somatostatinreceptor agonists (33). In the case of galanin receptors, a tripeptide mimetic library based on the pharmacophores of galanin yielded the compound galnon, which, despite its low affinity and poor receptor-subtype selectivity, has rapidly become a tool in our studies on the role of galanin in seizures, cognition, pain, feeding, and opiate withdrawal (13)(14)(15).…”

Section: Discussionmentioning

confidence: 99%

Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests

Bartfai

Lü

Badie-Mahdavi

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

133

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The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GalR1 receptors (K i ‫؍‬ 34.2 M) and virtually no affinity for GalR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.G alanin, a 29-to 30-aa-long neuropeptide, has been shown to affect feeding, cognitive, and sexual behavior and to regulate seizure and pain thresholds when applied intraventricularly (1-3). Galanin actions are mediated through three G proteincoupled receptors present in the brain and the peripheral nervous system (4-6). Transgenic mice overexpressing galanin have much higher seizure thresholds (7), and the galanin receptor 1 (GalR1) Ϫ/Ϫ mice have spontaneous seizures, demonstrating the role of galanin and its receptor in seizure control (8). Despite the wealth of biological information on galanin signaling, no progress has been made in using the galanin-receptor subtypes as drug targets. The lack of progress is largely due to the poor results from random screening at several major pharmaceutical companies (9). More than 4 million compounds were screened, but no workable compounds for medicinal chemical optimization were identified. Both Johnson & Johnson (10) and Schering have published reports of compounds active at high micromolar concentrations that had stability problems, as well as other problems (9). The only nonpeptide galanin receptor ligand available is galnon, a substance intended to display analogs of the three major pharmacophores of galanin, Trp-2, Asn-5, and Tyr-9 (11, 12), on a linear, peptide-like backbone. Galnon is a lowaffinity, nonreceptor-subtype-selective agonist that acts at both GalR1-and GalR2-type receptors (13). Despite its serious shortcomings, galnon, within a year of its synthesis, was shown to affect behavioral symptoms and neurochemical correlates in opiate withdrawal (14), pain (15), and seizure (13) The present work describes the synthesis and ...

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Somatostatin analogs

Cited by 88 publications

References 106 publications

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

Somatostatin Subtype-2 Receptor-Targeted Metal-Based Anticancer Complexes

Functional and Binding Characterizations of Urotensin II-Related Peptides in Human and Rat Urotensin II-Receptor Assay

Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests

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