Unexpected antinociceptive potency of cyclic [D-Tca1]CTAP: potential for a novel mechanism of action

Peter J. Horan, Kenneth D. Wild, Wieslaw W. Kazmierski, Ronald Ferguson, Victor J. Hruby, Steven J. Weber, Thomas P. Davis, Lei Fang, Richard J. Knapp, Henry I. Yamamura, Thomas H. Kramer, Thomas F. Burks, Wayne D. Bowen, A. E. Takemori, Frank Porreca

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16 Scopus citations


This study tested the hypothesis that compounds which may bind simultaneously to δ and μ receptors may be more potent antinociceptive agents than would be predicted from their bindings affinities at individual μ and δ opioid receptors. D-Tca-Cys- Tyr-D-Trp-Arg-Thr-Pen-Thr-NH2 ([D-Tca1]CTAP) where D-Ta is a cyclic D-trytophan analogue) was synthesized and evaluated in radioligand competition assays, opioid bioassays, and in an antinociceptive assay (the tail-flick test in mice). Additionally, the metabolic stability of [D-Tca1]CTAP was evaluated in striatal and cerebellar tissue slices. In the rat brain in vitro, [D-Tca1]CTAP competed weakly for sites labelled by [3H]D-Phe-Cys-Tyr-D-Trp-Om-Thr-Pen-Thr-NH2 ([3H]CTOP) (μ-ligand), and [3H][D-Pen2, pCl-Phe5]enkephalin (δ-ligand); [D-Pen2, D-Pen5]enkephalin (DPDPE) (δ-agonist) was 6.5-fold less and 230-fold more potent, respectively, against these ligands. Additionally, in mouse isolated vas deferens and guinea pig isolated ileum smooth muscle preparations, [D-Tca1]CTAP proved to be weak as either a δ(IC50 of approximately 2 μM) or μ (IC50 > 8 μM) receptor agonist. Surprisingly, however, i.c.v. [D-Tca1]CTAP produced antinociception with potency no similar to DPDPE. The antinociceptive actions of [D-Tca1]CTAP were apparently not due to a metabolite or the release of endogeneous opiods, as this compound proved stable in both striatal and cerebellar tissue slices and its antinociceptive actions were not enhance by the 'enkephalinase' inhibitor thiorphan. The suggestion that [D-Tca1]CTAP might be acting by binding simultaneously go μ and δ receptors to produced its antinociceptive effect is supported by the demonstrated antagonism resulting from μ receptor blockade with either β-funaltrexamine (β-FNA) or naloxonazine, or by δ receptor blockade by ICI 174,864 ([N,N-dially-Tyr1, Aib2,3,Leu5] enkephalin). Furthermore, the antinociceptive properties of [D-Tca1]CTAP were antagonized by (naltrindole-5′-isothiocyanate) (5′-NTII), an antagonist at the δ2 opioid receptor subtype, but not by the δ1 antagonist [D-Ala2, D-Leu5, Cys6]enkephalin (DALCE). Additionally, no antagonism was produced by nor-binaltorphimine (nor-BNI), a κ antagonist. From these data, [D-Tca1]CTAP appears to bind to μ, and 5′-NTII-sensitive δ2, opioid receptors, and may represent the first of a class of compounds which may act at an opioid recptor complex via 'self-potentiation'.

Original languageEnglish (US)
Pages (from-to)53-62
Number of pages10
JournalEuropean Journal of Pharmacology
Issue number1
StatePublished - Mar 16 1993


  • Antinociception
  • Metabolism
  • Opioid receptor antagonists
  • δ-Opioid receptors
  • μ-Opioid receptors

ASJC Scopus subject areas

  • Pharmacology


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