Cyclic dermorphin tetrapeptide analogues obtained via ring-closing metathesis.
The dermorphin-derived cyclic tetrapeptide analogues H-Tyr-c[D-Cys-Phe-Cys]NH(2) and H-Tyr-c[D-Cys-Phe-D-Cys]NH(2) are opioid agonists at the mu and delta 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 -CH(2)-CH(2)- bridged peptides. In comparison with the cystine-containing parent peptides, all olefinic peptides showed significantly reduced mu and delta agonist potencies in the guinea pig ileum and mouse vas deferens assays. The -CH(2)-CH(2)-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 -CH(2)-CH(2)- 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.
Berezowska
Irena
I
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal,Quebec, Canada.
Chung
Nga N
NN
Lemieux
Carole
C
Wilkes
Brian C
BC
Schiller
Peter W
PW
D000501:Allylglycine / Q000737:chemistry; D000818:Animals; D002626:Chemistry, Pharmaceutical; D006168:Guinea Pigs; D007082:Ileum / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008297:Male; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry*; D010455:Peptides / Q000737:chemistry*; D014649:Vas Deferens / Q000378:metabolism
D018847:Opioid Peptides; D010455:Peptides; D000501:Allylglycine; C030058:dermorphin