Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis

• Autorzy: Berezowska I. , Chung N.N. , Lemieux C. , Wilkes B.C. , Schiller P.W.
• Języki publikacji: EN

Abstrakty

EN

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.

Słowa kluczowe

EN

opioid activity profile; cyclic dermorphin analogue; dermorphin; opioid peptide; in vitro; ring-closing metathesis

• Wydawca: -
• Czasopismo: Acta Biochimica Polonica
• Rocznik: 2006
• Tom: 53
• Numer: 1
• Opis fizyczny: p.73-76,fig.,ref.

Twórcy

autor

Berezowska I.

• Clinical Research Institute of Montreal, Montreal, Quebec, Canada

autor

Chung N.N.

autor

Lemieux C.

autor

Wilkes B.C.

autor

Schiller P.W.

Bibliografia

• Ahn YM, Yang KL, Georg GI (2001) A convenient method for the efficient removal of ruthenium by-products generated during olefin metathesis reactions. Org Lett 3: 1411–1413.
• Chen H, Chung NN, Lemieux C, Zelent B, Vanderkooi JM, Gryczynski I, Wilkes BC, Schiller PW (2005) [Aladan3]TIPP: a fluorescent δ opioid antagonist with high δ receptor binding affinity and δ selectivity. Biopolymers (Peptide Science) 80: 325–331.
• DiMaio J, Nguyen TM-D, Lemieux C, Schiller PW (1982) Synthesis and pharmacological characterization in vitro of cyclic enkephalin analogues: effects of conformational constraints on opiate receptor selectivity. J Med Chem 25: 1432–1438.
• Keller O, Rudinger J (1974) Synthesis of [1,6-α,α’-diaminosuberic acid]oxytocin (‘Dicarba’-oxytocin). Helv Chim Acta 57: 1253–1259.
• Nutt RF, Veber DF, Saperstein R (1980) Synthesis of nonreducible bicyclic analogs of somatostatin. J Am Chem Soc 102: 6539–6545.
• Schiller PW, Lipton A, Horrobin DF, Bodanszky M (1978) Unsulfated C-terminal 7-peptide of cholecystokinin: a new ligand of the opiate receptor. Biochem Biophys Res Commun 85: 1332–1338.
• Schiller PW, Nguyen TM-D, Maziak LA, Wilkes BC, Schiller PW (1987) Structure-activity relationships of cyclic opioid peptide analogues containing a phenylalanine residue in the 3-position. J Med Chem 30: 2094–2099.
• Stymiest JL, Mitchell BF, Wong S, Vederas JC (2003) Synthesis of biologically active dicarba analogues of the peptide hormone oxytocin using ring-closing metathesis. Org Lett 5: 47–49.
• Waterfield AA, Leslie FM, Lord JAH, Ling N, Kosterlitz HW (1979) Opioid activities of fragments of β-endorphin and of its leucine65-analogue. Comparison of the binding properties of methionine- and leucine-enkephalin. Eur J Pharmacol 58: 11–18.
• Wilkes BC, Schiller PW (1990) Conformation-activity relationships of cyclic dermorphin analogues. Biopolymers 29: 89–95.