Potent Antagonists of Somatostatin:  Synthesis and Biology

Hocart, Simon J.; Jain, Rahul; Murphy, William A.; Taylor, John E.; Morgan, Barry A.; Coy, David H.

doi:10.1021/jm970730q

Cited by 49 publications

(56 citation statements)

References 34 publications

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“…The data were obtained from two independent laboratories as a way to compare the biological data from different cell lines and different radioligands. The two datasets show similar results for the majority of the compounds, with some variabilities noted at hsst 3 or hsst 5 , as illustrated by the very similar values obtained in membranes of rat cortex for both sst1 and sst2 receptors (Table III), 18,19 when compared to the values obtained with recombinant human sst1 and sst2 receptors. 20,21 Typical of cyclic octapeptide analogs, the majority of our compounds showed binding to the hsst2, hsst3, and hsst5 receptors, with little or no affinity for the hsst1 or hsst4 receptors.…”

Section: Binding Affinities To the Somatostatin Receptorssupporting

confidence: 62%

“…Although the potencies are still rather low, these results could represent a breakthrough in somatostatin research. [5][6][7] The synthetic somatostatin analog octreotide (Sandostatin, SMS 201-995) 8 has been studied extensively because of its therapeutic utility in the treatment of acromegaly. Octreotide provides significant therapeutic utility by producing a prolonged effect in the target organs, as a result of a much longer biological half-life.…”

Section: Introductionmentioning

confidence: 99%

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Syntheses and biological activities of sandostatin analogs containing stereochemical changes in positions 6 or 8

et al. 2000

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In a continuation of our research efforts on the design and synthesis of novel peptidomimetic structures, we have synthesized a series of sandostatin amide analogs in which stereoisomers of threonine and β‐hydroxyvaline(β‐Hyv) are employed. The analogs D‐Phe1‐c[Cys2‐Phe3‐D‐Trp4‐Lys5‐Xaa6‐Cys7]‐Xbb8‐NH2 (Xaa = allo‐Thr, D‐allo‐Thr , D‐β‐Hyv, β‐Hyv, D‐Thr, and Xbb = Thr or Xaa = Thr and Xbb = allo‐Thr, D‐allo‐Thr , β‐Hyv, D‐Thr ) explore the effects on biological activity of stereochemical modifications and β‐methylation at positions 6 or 8. By these modifications, we examine the role of the two residues in binding to somatostatin receptors. We describe the synthesis and biological activity of these analogs. In combination with the results of the conformational analysis, this study provides new insights into the structural requirements for the binding affinity of somatostatin amide analogs to somatostatin receptors [Mattern et al., Conformational analyses of sandostatin analogs containing stereochemical changes in positions 6 or 8]. © 2000 John Wiley & Sons, Inc. Biopoly 53: 497–505, 2000

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Section: Binding Affinities To the Somatostatin Receptorssupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Syntheses and biological activities of sandostatin analogs containing stereochemical changes in positions 6 or 8

et al. 2000

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“…See legend toFigure 3for other designations. * * * P , 0:001 vs UII(42,44, 46 and 47, respectively) or UII-NH 2 (43, 45 and 48, respectively) by one-way ANOVA followed by post hoc Dunnett's test, NS, not statistically significant.…”

mentioning

confidence: 94%

Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction

Labarrère

Chatenet

Leprince

et al. 2003

Journal of Enzyme Inhibition and Medicinal Chemistry

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The sequence of human urotensin II (UII) has been recently established as H-Glu-Thr-Pro-Asp-Cys-Phe-Trp-Lys-Tyr-Cys-Val-OH, and it has been reported that UII is the most potent mammalian vasoconstrictor peptide identified so far. A series of UII analogues was synthesized, and the contractile activity of each compound was studied in vitro using de-endothelialised rat aortic rings. Replacement of each amino acid by an L-alanine or by a D-isomer showed that the N- and C-terminal residues flanking the cyclic region of the amidated peptide were relatively tolerant to substitution. Conversely, replacement of any residue of the cyclic region significantly reduced the contractile activity of the molecule. The octapeptide UII(4-11) was 4 times more potent than UII, indicating that the C-terminal region of the molecule possesses full biological activity. Alanine or D-isomer substitutions in UII(4-11) or in UII(4-11)-NH2, respectively, showed a good correlation with the results obtained for UII-NH2. Disulfide bridge disruption or replacement of the cysteine residues by their D-enantiomers markedly reduced the vasoconstrictor effect of UII and its analogues. In contrast, acetylation of the N-terminal residue of UII and UII-NH2 enhanced the potency of the peptide. Finally, monoiodination of the Tyr6 residue in UII(4-11) increased by 5 fold the potency of the peptide in the aortic ring bioassay. This structure-activity relationship study should provide useful information for the rational design of selective and potent UII receptor agonists and antagonists.

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“…The first compound with antagonistic effects of somatostatin, c[Ahep-Phe-DTrp-Lys-Thr(Bzl)] ( Table 5, (26)) unexpectedly emerged during attempts to synthesise the Bzl-deprotected form of the pentapeptide. Initial studies showed that this peptide blocked the inhibitory effects of somatostatin on growth hormone, insulin, and glucagon release at low doses, but turned out to be an agonist at higher doses [187,188]. Some years later, Bass et al introduced disulfide-linked cyclic octapeptide antagonists which contained a DCys in position 6 and LCys in position 27 -Ac-(4-NO 2 -Phe)-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 [189] 28 DC-38-48 Nal-c(DCys-Pal-DTrp-Lys-Val-Cys)-Nal-NH 2 [188] 29 PRL-2970 Cpa-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-Nal-NH 2 [190] 30 PRL-2915 Nal-c(DCys-Pal-DTrp-Lys-Tle-Cys)-Nal-NH 2 [190] 31 AC-178,335 Ac-DHis-DPhe-DIle-DArg-DTrp-DPhe-NH 2 [191] Abbrevation: Ahp, 7-aminoheptanoyl; Nal, 3-(2-naphthyl)alanine; Cpa, 4-chlorophenylalanine; Pal, 3-pyridylalanine; Tle, tert.-leucine; 11 relative to SRIF.…”

Section: Somatostatin Antagonistsmentioning

confidence: 99%

“…Initial studies showed that this peptide blocked the inhibitory effects of somatostatin on growth hormone, insulin, and glucagon release at low doses, but turned out to be an agonist at higher doses [187,188]. Some years later, Bass et al introduced disulfide-linked cyclic octapeptide antagonists which contained a DCys in position 6 and LCys in position 27 -Ac-(4-NO 2 -Phe)-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 [189] 28 DC-38-48 Nal-c(DCys-Pal-DTrp-Lys-Val-Cys)-Nal-NH 2 [188] 29 PRL-2970 Cpa-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-Nal-NH 2 [190] 30 PRL-2915 Nal-c(DCys-Pal-DTrp-Lys-Tle-Cys)-Nal-NH 2 [190] 31 AC-178,335 Ac-DHis-DPhe-DIle-DArg-DTrp-DPhe-NH 2 [191] Abbrevation: Ahp, 7-aminoheptanoyl; Nal, 3-(2-naphthyl)alanine; Cpa, 4-chlorophenylalanine; Pal, 3-pyridylalanine; Tle, tert.-leucine; 11 relative to SRIF. One peptide (27) displayed high affinity binding to sst2 comparable to native somatostatin but reversed the somatostatin-mediated cAMP accumulation in rat somatomammotroph GH 4 C 1 cells as well as SRIFstimulated growth of sst2 expressing yeast cells.…”

Section: Somatostatin Antagonistsmentioning

confidence: 99%

Development of Conformationally Restricted Analogues of Bradykinin and Somatostatin Using Constrained Amino Acids and Different Types of Cyclization

Reißmann

Imhof²

2004

CMC

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The structure-based design of peptide drugs requires the knowledge of the bioactive conformation. Studies on this receptor-bound 3D structure require linear or cyclic analogues with strongly reduced flexibility, but high biological activity, since only analogues with retained potency have preserved the bioactive conformation. Constrained amino acids containing double bonds or bulky substituents at the N(alpha)-, C(alpha)- and C(beta)-atom as well as at the aromatic ring atom were successfully applied to obtain potent and stable analogues of bradykinin and somatostatin, which due to their restricted conformation were suitable objects for conformational studies. Besides the generation of constrained cyclic analogues with improved biological and pharmacological properties, cyclic peptides were used as convenient models for the study of turn formations. Cyclization of the linear peptide bradykinin was performed by linking the N-terminus and the C-terminus, and in both bradykinin and somatostatin by cyclization using the amino acid side chains and by backbone cyclization. The later requires the introduction of N(alpha)-functionalised amino acids for ring closure which can be performed either through incorporation of N(alpha)-functionalised amino acids or dipeptide building units. Conformational analysis of a cyclic bradykinin analogue by means of NMR-studies together with molecular dynamics simulation led to a quasicyclic 3D structure with two turns and together with other 3D structures provided a pharmacophore model of bradykinin antagonists.

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Potent Antagonists of Somatostatin: Synthesis and Biology

Cited by 49 publications

References 34 publications

Syntheses and biological activities of sandostatin analogs containing stereochemical changes in positions 6 or 8

Syntheses and biological activities of sandostatin analogs containing stereochemical changes in positions 6 or 8

Structure–Activity Relationships of Human Urotensin II and Related Analogues on Rat Aortic Ring Contraction

Development of Conformationally Restricted Analogues of Bradykinin and Somatostatin Using Constrained Amino Acids and Different Types of Cyclization

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