Design and Synthesis of Somatostatin Analogues with Topographical Properties That Lead to Highly Potent and Specific μ Opioid Receptor Antagonists with Greatly Reduced Binding at Somatostatin Receptors

Wieslaw Kazmierski, William S. Wire, George K. Lui, Richard J. Knapp, Jennifer E. Shook, Thomas F. Burks, Henry I. Yamamura, Victor J. Hruby

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Abstract

A series of conformationally restricted, cyclic octapeptides containing a conformationally stable tetrapeptide sequence related to somatostatin, -Tyr-D-Trp-Lys-Thr-, as a template, were designed and synthesized with the goal of developing highly potent and selective μ opioid antagonists with minimal or no somatostatin-like activity. Three distinct structures of the peptide became targets of chemical modifications and constraints; the N- and C-terminal amino acids and the cyclic 20-membered ring moiety. Based on the conformational analysis of active and inactive analogues of the parent peptide (formula omitted), CTP (Kazmierski, W.; Hruby, V. J. Tetrahedron 1988, 44, 697-710), we designed analogues to include the tetrahydroisoquinolinecarboxylate (Tic) moiety as the N-terminal amino acid instead of D-Phe, since Tic can exist only as a gauche (-) or a gauche (+) conformer. In this series, the following peptides were synthesized and pharmacologically evaluated: (formula omitted). In rat brain membrane opioid radioligand binding assays, all three peptides displayed high affinity for μ opioid receptors (IC50 = 1.2, 1.4, 1.2 nM, respectively), and exceptional μ vs δopioid receptor selectivity: 7770, 11396, and 1060, respectively. TCTOP and TCTAP also possess exceptional μ vs somatostatin receptor selectivity: 14574 and 28613, respectively. In the peripheral in vitro GPI bioassay, TCTP, TCTOP, and TCTAP were highly effective antagonists of the potent μ opioid receptor agonist PL017, with pA2 = 8.69 for TCTAP, 8.10 for TCTP, and 7.38 for TCTOP. Our results show that a 10-fold higher affinity and selectivity for μ opioid receptors (in both central and peripheral studies) over δ and somatostatin receptor was gained as a result of the D-Tic1 substitution. These three peptides, TCTP, TCTOP, and TCTAP, are the most potent and selective μ opioid antagonists known. CTP has been shown to possess prolonged biological action, much longer than that of naloxone. This renders these analogues potentially useful ligands for investigating the physiological functions of the μ opioid receptor. Analogues of TCTP in which the 20-membered disulfide ring was contracted by deletion of D-Trp4, and/or Lys5, and/or Thr6 led to compounds with greatly reduced potency at the μ opioid receptor. Furthermore, modification of the Thr8 residue with Val, Ser, Asn, and Asp or by simple deletion of the residue led to analogues with greatly reduced potency and reduced μ opioid receptor selectivity.

Original languageEnglish (US)
Pages (from-to)2170-2177
Number of pages8
JournalJournal of Medicinal Chemistry
Volume31
Issue number11
DOIs
StatePublished - Nov 1 1988

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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