Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis
Languages of publication
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.
- 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 non-reducible 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.
Publication order reference