Design and Synthesis of Conformationally Constrained Somatostatin Analogues with High Potency and Specificity for μ Opioid Receptors

John T. Pelton, Wieslaw Kazmierski, Victor J. Hruby, Karoly Gulya, Henry I. Yamamura

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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); o-Phe-Cys-Tyr-D-Trp-Lys-Gly-Pen-Thr-NH2 (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/IC50μ = 4000)for μ opioid receptors. Furthermore, 2 exhibited very low affinity for somatostatin receptors in the rat brain (IC50 > 24000 nM), with an IC50 somatostatin/IC50μ 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 (US)
Pages (from-to)2370-2375
Number of pages6
JournalJournal of Medicinal Chemistry
Issue number11
StatePublished - Jan 1 1986


ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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