Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for μ opioid receptors

John T. Pelton, Wieslaw Kazmierski, Karoly Gulya, K. Gulya, Victor J. Hruby

Research output: Contribution to journalArticle

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Abstract

A series of cyclic, conformationally constrained peptides related to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the μ opioid receptor. The following new peptides were prepared and tested for their μ opioid receptor potency and selectivity in rat brain binding assays: D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (2, CTOP); D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (3, CTAP); D-Phe-Cys-Tyr-D-Trp-Nle-Thr-Pen-Thr-NH2 (4); D-Phe-Cys-Tyr-D-Trp-Lys-Val-Pen-Thr-NH2 (5); D-Phe-Cys-Tyr-D-Trp-Lys-Gly-Pen-Thr-NH 2(6);D-Phe-Cys-Tyr-Trp-Lys-Thr-Pen-Thr-NH2 (7); D-Tyr-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH (8); D-PhGly-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (9); and D-PhGly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH (10). The most selective peptide, 2 (CTOP), displayed both high affinity (IC50 = 3.5 nM) and exceptional selectivity (IC50 δ/IC50 μ = 4000) for μ opioid receptors. Furthermore, 2 exhibited very low affinity for somatostatin receptors in the rat brain (IC50 > 24 000 nM), with an IC50 somatostatin/IC50 μ receptor selectivity of 8750. These conformationally constrained cyclic peptides should provide new insight into the structural and conformational requirements for the μ opioid receptor and the physiological role of this receptor.

Original languageEnglish
Pages (from-to)2370-2375
Number of pages6
JournalJournal of Medicinal Chemistry
Volume29
Issue number11
Publication statusPublished - 1986

Fingerprint

Opioid Receptors
Somatostatin
Inhibitory Concentration 50
Somatostatin Receptors
Peptides
Rats
Brain
Cyclic Peptides
cysteinyltyrosine
Assays
Peptide Receptors
phenylalanyl-cyclo(cysteinyltyrosyl-tryptophyl-ornithyl-threonyl-penicillamine)threoninamide

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for μ opioid receptors. / Pelton, John T.; Kazmierski, Wieslaw; Gulya, Karoly; Gulya, K.; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 29, No. 11, 1986, p. 2370-2375.

Research output: Contribution to journalArticle

Pelton, John T. ; Kazmierski, Wieslaw ; Gulya, Karoly ; Gulya, K. ; Hruby, Victor J. / Design and synthesis of conformationally constrained somatostatin analogues with high potency and specificity for μ opioid receptors. In: Journal of Medicinal Chemistry. 1986 ; Vol. 29, No. 11. pp. 2370-2375.
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abstract = "A series of cyclic, conformationally constrained peptides related to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the μ opioid receptor. The following new peptides were prepared and tested for their μ opioid receptor potency and selectivity in rat brain binding assays: D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (2, CTOP); D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (3, CTAP); D-Phe-Cys-Tyr-D-Trp-Nle-Thr-Pen-Thr-NH2 (4); D-Phe-Cys-Tyr-D-Trp-Lys-Val-Pen-Thr-NH2 (5); D-Phe-Cys-Tyr-D-Trp-Lys-Gly-Pen-Thr-NH 2(6);D-Phe-Cys-Tyr-Trp-Lys-Thr-Pen-Thr-NH2 (7); D-Tyr-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH (8); D-PhGly-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (9); and D-PhGly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH (10). The most selective peptide, 2 (CTOP), displayed both high affinity (IC50 = 3.5 nM) and exceptional selectivity (IC50 δ/IC50 μ = 4000) for μ opioid receptors. Furthermore, 2 exhibited very low affinity for somatostatin receptors in the rat brain (IC50 > 24 000 nM), with an IC50 somatostatin/IC50 μ receptor selectivity of 8750. These conformationally constrained cyclic peptides should provide new insight into the structural and conformational requirements for the μ opioid receptor and the physiological role of this receptor.",
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N2 - A series of cyclic, conformationally constrained peptides related to somatostatin were designed and synthesized in an effort to develop highly selective and potent peptides for the μ opioid receptor. The following new peptides were prepared and tested for their μ opioid receptor potency and selectivity in rat brain binding assays: D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (2, CTOP); D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (3, CTAP); D-Phe-Cys-Tyr-D-Trp-Nle-Thr-Pen-Thr-NH2 (4); D-Phe-Cys-Tyr-D-Trp-Lys-Val-Pen-Thr-NH2 (5); D-Phe-Cys-Tyr-D-Trp-Lys-Gly-Pen-Thr-NH 2(6);D-Phe-Cys-Tyr-Trp-Lys-Thr-Pen-Thr-NH2 (7); D-Tyr-Cys-Tyr-D-Trp-Lys-Thr-Cys-Thr-OH (8); D-PhGly-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (9); and D-PhGly-Pen-Phe-D-Trp-Lys-Thr-Cys-Thr-OH (10). The most selective peptide, 2 (CTOP), displayed both high affinity (IC50 = 3.5 nM) and exceptional selectivity (IC50 δ/IC50 μ = 4000) for μ opioid receptors. Furthermore, 2 exhibited very low affinity for somatostatin receptors in the rat brain (IC50 > 24 000 nM), with an IC50 somatostatin/IC50 μ receptor selectivity of 8750. These conformationally constrained cyclic peptides should provide new insight into the structural and conformational requirements for the μ opioid receptor and the physiological role of this receptor.

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