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

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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 [D-Pen2,Pen5]DT I and [D-Pen2,Pen5,Nle6]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
Publication statusPublished - 1994

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ASJC Scopus subject areas

  • Organic Chemistry

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