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 Citations (Scopus)

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
StatePublished - 1994

Fingerprint

Opioid Receptors
Disulfides
Penicillamine
delta Opioid Receptor
Vas Deferens
Bioactivity
Ileum
Biological Assay
Cysteine
Assays
Guinea Pigs
Substitution reactions
Peptides
deltorphin
Ala(2)-deltorphin I

ASJC Scopus subject areas

  • Organic Chemistry

Cite this

Design of cyclic deltorphins and dermenkephalins with a disulfide bridge leads to analogues with high selectivity for δ-opioid receptors. / Misicka, Aleksandra; Lipkowski, Andrzej W.; Horvath, Robert; Davis, Peg; Yamamura, Henry I.; Porreca, Frank; Hruby, Victor J.

In: Journal of Medicinal Chemistry, Vol. 37, No. 1, 1994, p. 141-145.

Research output: Contribution to journalArticle

Misicka, Aleksandra ; Lipkowski, Andrzej W. ; Horvath, Robert ; Davis, Peg ; Yamamura, Henry I. ; Porreca, Frank ; Hruby, Victor J. / Design of cyclic deltorphins and dermenkephalins with a disulfide bridge leads to analogues with high selectivity for δ-opioid receptors. In: Journal of Medicinal Chemistry. 1994 ; Vol. 37, No. 1. pp. 141-145.
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