Design of Cyclic Deltorphins and Dermenkephalins with a Disulfide Bridge Leads to Analogues with High Selectivity for δ-Opioid Receptors

Aleksandra Misicka, Andrzej W. Lipkowski, Robert Horvath, Peg Davis, Henry I. Yamamura, Frank Porreca, Victor J. Hruby

Research output: Contribution to journalArticle

27 Scopus citations

Abstract

We earlier suggested that the low receptor selectivity observed for previously synthesized constrained analogues of deltorphin I (DT I) was the result of a reduction in the lipophilic surface of the C-terminal of the peptide. To confirm this prediction and to further test a previously proposed conformational model for bioactivity at delta opioid receptors, we have synthesized several new cyclic analogues with the general structure [d-Xaa2,Yaa5] deltorphin I and II in which Xaa2 is d-cysteine or d-penicillamine (d-Pen), and Yaa5 is an l-or d-penicillamine residue. Additional substitutions at positions 4,6, and 7 also were examined. The analogues were tested for binding to μ- and δ-opioid receptors and in mouse vas deferens and guinea pig ileum biological assays. The introduction of a lipophilic l-Pen in position 5 and d-Cys or d-Pen in position 2 resulted in a highly δ-selective series of analogues, which fully confirmed our prediction. The cyclic analogues [formula omitted] DT I and [formula omitted] DT I are among the most δ-selective analogues described thus far.

Original languageEnglish (US)
Pages (from-to)141-145
Number of pages5
JournalJournal of Medicinal Chemistry
Volume37
Issue number1
DOIs
StatePublished - Jan 1 1994

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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