Novel sst4-Selective Somatostatin (SRIF) Agonists. 2. Analogues with β-Methyl-3-(2-naphthyl)alanine Substitutions at Position 8

Judit Erchegyi, B. Penke, Lajos Simon, Scott Michaelson, Sandra Wenger, Beatrice Waser, Renzo Cescato, Jean Claude Schaer, Jean Claude Reubi, Jean Rivier

Research output: Contribution to journalArticle

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Abstract

We present a family of human sst4-selective, high-affinity (IC50 = 2-4 nM) cyclic somatostatin (SRIF) octapeptides. These peptides result from the substitution of DTrp8 in H-c[Cys 3-Phe6-Phe7-DTrp8-Lys 9-Thr10-Phe11-Cys14]-OH (SRIF numbering) (ODT-8) by one of the four conformationally biased stereoisomers of β-methyl-3-(2-naphthyl)alanine (β-Me2Nal). Whereas H-c[Cys-Phe-Phe-DNal-Lys-Thr-Phe-Cys]-OH (ODN-8, 2) has high affinity and marginal selectivity for human sst3 (Reubi et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 13973-13978), H-c[Cys-Phe-Tyr-D-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH (5) has high affinity for all sst's except for sst1; H-c[Cys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (6) has high affinity for sst4 (IC50 = 2.1 nM), with more than 50-fold selectivity toward the other receptors. Analogues 7 and 8, containing D- and L-erythro-β-Me2Nal instead of the corresponding threo derivatives at position 8, are essentially inactive at all receptors. Substitution of Tyr7 in 5 and 6 by Aph7 resulted in 9 and 10 with similar affinity patterns overall yet lowered affinity. The substitution of DCys3 for Cys3 in 5 and 6 yielded H-c[DCys-Phe-Tyr-D-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (11) and H-c[DCys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (12), with biological profiles almost identical to those of their parents 5 and 6 (i.e., high affinity for sst2-5 for 11 and high affinity and selectivity for sst4 for 12). Analogue 12, with high sst4 affinity combined with the highest sst4 selectivity among all tested compounds, is an agonist in the cAMP accumulation assay (EC50 = 1.29 nM). Cold monoiodination of 12 yielded 14, with loss of sst4 selectivity and loss of high affinity (IC50 = 21 nM). Introduction of Tyr2 in 9 and 10 and substitution of Cys3 by DCys 3, to yield 15 and 16 (IC50 = 9.8 and 61 nM, respectively, for sst4 and limited selectivity), failed to generate a high-affinity 125iodinatable sst4-selective ligand. Substitution of Phe by Tyr at position 11 in H-c[DCys-Phe-Phe-L-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH yielded 18 (IC50 = 11.8 nM at sst 4), with limited sst4 selectivity (30-fold or greater at the other receptors) yet only slightly improved affinity over that of 14. Cold monoiodination of 18 yielded 20 (IC50 = 30 nM at sst4 and high selectivity). Whereas we were able, in this study, to identify a new family of sst4-selective, high-affinity compounds, our additional goal, to identify highly potent and sst4-selective ligands amenable to 125iodination, could not be achieved satisfactorily. On the other hand, some of the diastereomers identified in this study, such as 5, 11, 17, and 19, are very potent ligands at all receptors but sst1.

Original languageEnglish
Pages (from-to)5587-5596
Number of pages10
JournalJournal of Medicinal Chemistry
Volume46
Issue number26
DOIs
Publication statusPublished - Dec 18 2003

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Somatostatin
Inhibitory Concentration 50
Substitution reactions
Ligands
phenylalanylphenylalanine
Stereoisomerism
Assays
3-(2-naphthyl)alanine
Derivatives
Peptides

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Novel sst4-Selective Somatostatin (SRIF) Agonists. 2. Analogues with β-Methyl-3-(2-naphthyl)alanine Substitutions at Position 8. / Erchegyi, Judit; Penke, B.; Simon, Lajos; Michaelson, Scott; Wenger, Sandra; Waser, Beatrice; Cescato, Renzo; Schaer, Jean Claude; Reubi, Jean Claude; Rivier, Jean.

In: Journal of Medicinal Chemistry, Vol. 46, No. 26, 18.12.2003, p. 5587-5596.

Research output: Contribution to journalArticle

Erchegyi, J, Penke, B, Simon, L, Michaelson, S, Wenger, S, Waser, B, Cescato, R, Schaer, JC, Reubi, JC & Rivier, J 2003, 'Novel sst4-Selective Somatostatin (SRIF) Agonists. 2. Analogues with β-Methyl-3-(2-naphthyl)alanine Substitutions at Position 8', Journal of Medicinal Chemistry, vol. 46, no. 26, pp. 5587-5596. https://doi.org/10.1021/jm0302445
Erchegyi, Judit ; Penke, B. ; Simon, Lajos ; Michaelson, Scott ; Wenger, Sandra ; Waser, Beatrice ; Cescato, Renzo ; Schaer, Jean Claude ; Reubi, Jean Claude ; Rivier, Jean. / Novel sst4-Selective Somatostatin (SRIF) Agonists. 2. Analogues with β-Methyl-3-(2-naphthyl)alanine Substitutions at Position 8. In: Journal of Medicinal Chemistry. 2003 ; Vol. 46, No. 26. pp. 5587-5596.
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title = "Novel sst4-Selective Somatostatin (SRIF) Agonists. 2. Analogues with β-Methyl-3-(2-naphthyl)alanine Substitutions at Position 8",
abstract = "We present a family of human sst4-selective, high-affinity (IC50 = 2-4 nM) cyclic somatostatin (SRIF) octapeptides. These peptides result from the substitution of DTrp8 in H-c[Cys 3-Phe6-Phe7-DTrp8-Lys 9-Thr10-Phe11-Cys14]-OH (SRIF numbering) (ODT-8) by one of the four conformationally biased stereoisomers of β-methyl-3-(2-naphthyl)alanine (β-Me2Nal). Whereas H-c[Cys-Phe-Phe-DNal-Lys-Thr-Phe-Cys]-OH (ODN-8, 2) has high affinity and marginal selectivity for human sst3 (Reubi et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 13973-13978), H-c[Cys-Phe-Tyr-D-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH (5) has high affinity for all sst's except for sst1; H-c[Cys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (6) has high affinity for sst4 (IC50 = 2.1 nM), with more than 50-fold selectivity toward the other receptors. Analogues 7 and 8, containing D- and L-erythro-β-Me2Nal instead of the corresponding threo derivatives at position 8, are essentially inactive at all receptors. Substitution of Tyr7 in 5 and 6 by Aph7 resulted in 9 and 10 with similar affinity patterns overall yet lowered affinity. The substitution of DCys3 for Cys3 in 5 and 6 yielded H-c[DCys-Phe-Tyr-D-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (11) and H-c[DCys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (12), with biological profiles almost identical to those of their parents 5 and 6 (i.e., high affinity for sst2-5 for 11 and high affinity and selectivity for sst4 for 12). Analogue 12, with high sst4 affinity combined with the highest sst4 selectivity among all tested compounds, is an agonist in the cAMP accumulation assay (EC50 = 1.29 nM). Cold monoiodination of 12 yielded 14, with loss of sst4 selectivity and loss of high affinity (IC50 = 21 nM). Introduction of Tyr2 in 9 and 10 and substitution of Cys3 by DCys 3, to yield 15 and 16 (IC50 = 9.8 and 61 nM, respectively, for sst4 and limited selectivity), failed to generate a high-affinity 125iodinatable sst4-selective ligand. Substitution of Phe by Tyr at position 11 in H-c[DCys-Phe-Phe-L-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH yielded 18 (IC50 = 11.8 nM at sst 4), with limited sst4 selectivity (30-fold or greater at the other receptors) yet only slightly improved affinity over that of 14. Cold monoiodination of 18 yielded 20 (IC50 = 30 nM at sst4 and high selectivity). Whereas we were able, in this study, to identify a new family of sst4-selective, high-affinity compounds, our additional goal, to identify highly potent and sst4-selective ligands amenable to 125iodination, could not be achieved satisfactorily. On the other hand, some of the diastereomers identified in this study, such as 5, 11, 17, and 19, are very potent ligands at all receptors but sst1.",
author = "Judit Erchegyi and B. Penke and Lajos Simon and Scott Michaelson and Sandra Wenger and Beatrice Waser and Renzo Cescato and Schaer, {Jean Claude} and Reubi, {Jean Claude} and Jean Rivier",
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T1 - Novel sst4-Selective Somatostatin (SRIF) Agonists. 2. Analogues with β-Methyl-3-(2-naphthyl)alanine Substitutions at Position 8

AU - Erchegyi, Judit

AU - Penke, B.

AU - Simon, Lajos

AU - Michaelson, Scott

AU - Wenger, Sandra

AU - Waser, Beatrice

AU - Cescato, Renzo

AU - Schaer, Jean Claude

AU - Reubi, Jean Claude

AU - Rivier, Jean

PY - 2003/12/18

Y1 - 2003/12/18

N2 - We present a family of human sst4-selective, high-affinity (IC50 = 2-4 nM) cyclic somatostatin (SRIF) octapeptides. These peptides result from the substitution of DTrp8 in H-c[Cys 3-Phe6-Phe7-DTrp8-Lys 9-Thr10-Phe11-Cys14]-OH (SRIF numbering) (ODT-8) by one of the four conformationally biased stereoisomers of β-methyl-3-(2-naphthyl)alanine (β-Me2Nal). Whereas H-c[Cys-Phe-Phe-DNal-Lys-Thr-Phe-Cys]-OH (ODN-8, 2) has high affinity and marginal selectivity for human sst3 (Reubi et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 13973-13978), H-c[Cys-Phe-Tyr-D-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH (5) has high affinity for all sst's except for sst1; H-c[Cys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (6) has high affinity for sst4 (IC50 = 2.1 nM), with more than 50-fold selectivity toward the other receptors. Analogues 7 and 8, containing D- and L-erythro-β-Me2Nal instead of the corresponding threo derivatives at position 8, are essentially inactive at all receptors. Substitution of Tyr7 in 5 and 6 by Aph7 resulted in 9 and 10 with similar affinity patterns overall yet lowered affinity. The substitution of DCys3 for Cys3 in 5 and 6 yielded H-c[DCys-Phe-Tyr-D-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (11) and H-c[DCys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (12), with biological profiles almost identical to those of their parents 5 and 6 (i.e., high affinity for sst2-5 for 11 and high affinity and selectivity for sst4 for 12). Analogue 12, with high sst4 affinity combined with the highest sst4 selectivity among all tested compounds, is an agonist in the cAMP accumulation assay (EC50 = 1.29 nM). Cold monoiodination of 12 yielded 14, with loss of sst4 selectivity and loss of high affinity (IC50 = 21 nM). Introduction of Tyr2 in 9 and 10 and substitution of Cys3 by DCys 3, to yield 15 and 16 (IC50 = 9.8 and 61 nM, respectively, for sst4 and limited selectivity), failed to generate a high-affinity 125iodinatable sst4-selective ligand. Substitution of Phe by Tyr at position 11 in H-c[DCys-Phe-Phe-L-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH yielded 18 (IC50 = 11.8 nM at sst 4), with limited sst4 selectivity (30-fold or greater at the other receptors) yet only slightly improved affinity over that of 14. Cold monoiodination of 18 yielded 20 (IC50 = 30 nM at sst4 and high selectivity). Whereas we were able, in this study, to identify a new family of sst4-selective, high-affinity compounds, our additional goal, to identify highly potent and sst4-selective ligands amenable to 125iodination, could not be achieved satisfactorily. On the other hand, some of the diastereomers identified in this study, such as 5, 11, 17, and 19, are very potent ligands at all receptors but sst1.

AB - We present a family of human sst4-selective, high-affinity (IC50 = 2-4 nM) cyclic somatostatin (SRIF) octapeptides. These peptides result from the substitution of DTrp8 in H-c[Cys 3-Phe6-Phe7-DTrp8-Lys 9-Thr10-Phe11-Cys14]-OH (SRIF numbering) (ODT-8) by one of the four conformationally biased stereoisomers of β-methyl-3-(2-naphthyl)alanine (β-Me2Nal). Whereas H-c[Cys-Phe-Phe-DNal-Lys-Thr-Phe-Cys]-OH (ODN-8, 2) has high affinity and marginal selectivity for human sst3 (Reubi et al., Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 13973-13978), H-c[Cys-Phe-Tyr-D-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH (5) has high affinity for all sst's except for sst1; H-c[Cys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (6) has high affinity for sst4 (IC50 = 2.1 nM), with more than 50-fold selectivity toward the other receptors. Analogues 7 and 8, containing D- and L-erythro-β-Me2Nal instead of the corresponding threo derivatives at position 8, are essentially inactive at all receptors. Substitution of Tyr7 in 5 and 6 by Aph7 resulted in 9 and 10 with similar affinity patterns overall yet lowered affinity. The substitution of DCys3 for Cys3 in 5 and 6 yielded H-c[DCys-Phe-Tyr-D-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (11) and H-c[DCys-Phe-Tyr-L-threo-β-Me2Nal-Lys-Thr-Phe-Cys]-OH (12), with biological profiles almost identical to those of their parents 5 and 6 (i.e., high affinity for sst2-5 for 11 and high affinity and selectivity for sst4 for 12). Analogue 12, with high sst4 affinity combined with the highest sst4 selectivity among all tested compounds, is an agonist in the cAMP accumulation assay (EC50 = 1.29 nM). Cold monoiodination of 12 yielded 14, with loss of sst4 selectivity and loss of high affinity (IC50 = 21 nM). Introduction of Tyr2 in 9 and 10 and substitution of Cys3 by DCys 3, to yield 15 and 16 (IC50 = 9.8 and 61 nM, respectively, for sst4 and limited selectivity), failed to generate a high-affinity 125iodinatable sst4-selective ligand. Substitution of Phe by Tyr at position 11 in H-c[DCys-Phe-Phe-L-threo-β -Me2Nal-Lys-Thr-Phe-Cys]-OH yielded 18 (IC50 = 11.8 nM at sst 4), with limited sst4 selectivity (30-fold or greater at the other receptors) yet only slightly improved affinity over that of 14. Cold monoiodination of 18 yielded 20 (IC50 = 30 nM at sst4 and high selectivity). Whereas we were able, in this study, to identify a new family of sst4-selective, high-affinity compounds, our additional goal, to identify highly potent and sst4-selective ligands amenable to 125iodination, could not be achieved satisfactorily. On the other hand, some of the diastereomers identified in this study, such as 5, 11, 17, and 19, are very potent ligands at all receptors but sst1.

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