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Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis

100%

Berezowska I., Chung N. N., Lemieux C., Wilkes B. C., Schiller P. W.

2006

vol. 53

issue 1

73-76

The dermorphin-derived cyclic tetrapeptide analogues H-Tyr-c[d-Cys-Phe-Cys]NH2 and H-Tyr-c[d-Cys-Phe-D-Cys]NH2 are opioid agonists at the µ and δ receptor. To enhance the metabolic stability of these peptides, we replaced the disulfide bridge with a bis-methylene moiety. This was achieved by solid-phase synthesis of the linear precursor peptide containing allylglycine residues in place of the Cys residues, followed by ring-closing metathesis. In the case of the peptide with L-configuration in the 4-position both the cis and the trans isomer of the resulting olefinic peptides were formed, whereas the cis isomer only was obtained with the peptide having the d-configuration in position 4. Catalytic hydrogenation yielded the saturated -CH2-CH2- bridged peptides. In comparison with the cystine-containing parent peptides, all olefinic peptides showed significantly reduced µ and δ agonist potencies in the guinea pig ileum and mouse vas deferens assays. The -CH2-CH2-bridged peptide with l-configuration in the 4-position was equipotent with its cystine-containing parent in both assays, whereas the bis-methylene analogue with d-configuration in position 4 was 10-27-fold less potent compared to its parent. The effect of the disulfide replacements with the -CH=CH- and-CH2-CH2- moieties on the conformational behavior of these peptides was examined by theoretical conformational analysis which provided plausible explanations in terms of structural parameters for the observed changes in opioid activity.

Dansylated analogues of the opioid peptide [Dmt1]DALDA: in vitro activity profiles and fluorescence parameters.

86%

Berezowska I., Lemieux C., Chung N. N., Zelent B., Schiller P. W.

vol. 51

issue 1

107-113

Dansylated analogues of the potent and selective μ opioid peptide agonist [Dmt1]DALDA (H-Dmt-D-Arg-Phe-Lys-NH2; Dmt = 2',6'-dimethyltyrosine) were prepared either by substitution of Nβ-dansyl-α,β-diaminopropionic acid or Nε-dansyllysine for Lys4, or by attachment of a dansyl group to the C-terminal carboxamide function via a linker. All three analogues displayed high μ agonist potency in vitro and the C-terminally dansylated one retained significant μ receptor selectivity. The three analogues showed interesting differences in their fluorescence emission maxima and quantum yields, indicating that the dansyl group in two of them was engaged in intramolecular hydrophobic interactions. These dansylated [Dmt1]DALDA analogues represent valuable tools for binding studies, cellular uptake and intracellular distribution studies, and tissue distribution studies.

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2 Acta Biochimica Polonica

1 2006

1 2004

2 Berezowska I.

2 Chung N. N.

2 Lemieux C.

2 Schiller P. W.

1 Wilkes B. C.

1 Zelent B.

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Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis

Dansylated analogues of the opioid peptide [Dmt1]DALDA: in vitro activity profiles and fluorescence parameters.