Agonist and antagonist profiles of [D-Ala2, Glu4]deltorphin and its [Cys4]- and [Ser4]-substituted derivatives: Further evidence of opioid delta receptor multiplicity

P. J. Horan, K. D. Wild, A. Misicka, A. Lipkowski, R. C. Haaseth, V. J. Hruby, S. J. Weber, T. P. Davis, H. I. Yamamura, F. Porreca

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25 Scopus citations


Pharmacological evidence has suggested the presence of two supraspinal opioid delta receptor subtypes in the mouse, termed delta-1 and delta-2. [D- Pen2, D-Pen5]enkephalin (DPDPE) is thought to be primarily an agonist at the opioid delta-1 subtype, whereas H2N-Tyr-D-Ala-Phe-Glu-Val-Val-Gly-NH2 ([D-Ala2, Glu4] deltorphin) is a selective agonist at the delta-2 subtype. Based on previous reports suggesting that a receptor sulfhydryl group may be critical for ligand binding to the opioid delta receptor, the present investigation has attempted to discover whether this concept extends to the opioid delta-2 receptor. For this purpose, a cysteine-substituted deltorphin was synthesized and the potential agonist and antagonist properties of this compound, H2N-Tyr-D-Ala-Phe-Cys-Val-Val-Gly-NH2 ([D-Ala2, Cys4]deltorphin), were evaluated in an antinociceptive assay after i.c.v. administration to mice and stability in mouse brain was determined. As a control, a serine-substituted deltorphin was also prepared and the potential agonist and antagonist properties of this compound, H2N-Tyr-D-Ala-Phe-Ser- Val-Val-Gly-NH2 ([D-Ala2, Ser4]deltorphin, as well as those of the parent deltorphin, [D-Ala2, Glu4]deltorphin, were evaluated. Acutely, [D-Ala2, Cys4]deltorphin, [D-Ala2, Ser4]deltorphin and [D-Ala2, Glu4]deltorphin each produced dose-related antinociceptive effects. Pretreatment with a single i.c.v. injection of [D-Ala2, Cys4]deltorphin, [D-Ala2, Ser4]deltorphin or [D-Ala2, Glu4]deltorphin blocked the antinociceptive effects of [D-Ala2, Glu4]deltorphin (delta-2 agonist) for up to 24 hr, but not the antinociceptive effects of DPDPE (delta-1 agonist). Pretreatment with a single dose [D-Ser2, Leu5, Thr6]enkephalin (DSLET) (delta-2 agonist) failed to affect [D-Ala2, Glu4]deltorphin-mediated antinociception, suggesting that the antagonistic actions of the deltorphin derivatives were not due to the production of acute tolerance. From these data, we postulate that an intact thiol group is apparently not critical for the binding of these ligands at the opioid delta-2 receptor.

Original languageEnglish (US)
Pages (from-to)896-902
Number of pages7
JournalJournal of Pharmacology and Experimental Therapeutics
Issue number2
StatePublished - 1993

ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology


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