Novel peptidic Mu opioid antagonists: Pharmacologic characterization in vitro and in vivo

T. H. Kramer, J. E. Shook, W. Kazmierski, E. A. Ayres, W. S. Wire, V. J. Hruby, T. F. Burks

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148 Scopus citations


A series of six synthetic octapeptides, structurally related to somatostatin, demonstrate high affinity and selectivity for mu opioid receptors in radioligand binding assays. The compounds, D-Phe-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (CTP), D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP), D-Phe-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (CTAP), D-tetrahydroisoquinoline carboxylic acid (D-Tic)-Cys-Tyr-D-Trp-Lys-Thr-Pen-Thr-NH2 (Tic-CTP), D-Tic-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (D-Tic-CTOP) and D-Tic-Cys-Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 (D-Tic-CTAP), were tested in vitro and in vivo for agonist and antagonist potency and selectivity. In vitro bioassays included the guinea pig ileum, mouse vas deferens and rabbit vas deferens. In vivo tests included hotplate antinociception and gastrointestinal transit inhibition, performed in mice. In vitro, all six derivatives were competitive, highly selective mu antagonists (pA2 values from 6.4-7.9). The compounds demonstrated varying degrees of intrinsic agonist activity especially in the mouse vas deferens, the least active being CTAP and D-Tic-CTAP, which showed no mu or kappa agonist actions, and delta activity only at very high (>3 μM) concentrations. In vivo, none of these compounds showed antinociceptive actions when administered i.c.v. in mice. All were competitive mu antagonists in the hotplate antinociception test. Antagonist potency for all the derivatives was similar and approximately 10-fold greater than naloxone in this in vivo test (pA2 values from 11.2-11.9). CTAP and CTOP gave comparable results (competitive mu antagonism, lack of agonist activity) when administered intraspinally in the gastrointestinal transit inhibition test with apparent antagonist potency also approximately 10-fold greater than naloxone. (pA2 values of 11.4 and 11.3, respectively). At present, these compounds represent the most selective and potent mu opioid antagonists yet synthesized.

Original languageEnglish (US)
Pages (from-to)544-551
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1989
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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