A novel cyclic enkephalin analogue with potent opioid antagonist activity.
2',6'-Dimethyl substitution of the Tyr(1) residue in opioid agonist peptides and deletion of the N-terminal amino group, as achieved by replacement of Tyr(1) with 3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp), have been shown to produce opioid antagonists. To examine the effect of beta-methylation of Dhp(1) in opioid peptides on the activity profile, stereoselective syntheses of (3S)- and (3R)-3-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(3S)- and (3R)-Mdp] were carried out. In comparison with the cyclic parent antagonist peptide Dhp-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2), the methylated analogue (3S)-Mdp-c[D-Cys-Gly-Phe(pNO(2))-D-Cys]NH(2) showed higher micro, delta and kappa antagonist potencies in functional assays and higher binding affinities for micro, delta and kappa opioid receptors (K(i)(micro)=2.03 nM; K(i)(delta)=2.34 nM; K(i)(kappa)=49.5 nM), whereas the corresponding (3R)-Mdp(1)-analogue was less potent by 1-2 orders of magnitude.
Weltrowska
Grazyna
G
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, 110 Pine Avenue West, Montreal, Quebec, Canada H2W 1R7.
Lu
Yixin
Y
Lemieux
Carole
C
Chung
Nga N
NN
Schiller
Peter W
PW
D000818:Animals; D004745:Enkephalins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D008745:Methylation; D051379:Mice; D009292:Narcotic Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors / Q000378:metabolism; D017473:Receptors, Opioid, kappa / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000037:antagonists & inhibitors / Q000378:metabolism; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014649:Vas Deferens / Q000187:drug effects / Q000378:metabolism
D004745:Enkephalins; D009292:Narcotic Antagonists; D017465:Receptors, Opioid, delta; D017473:Receptors, Opioid, kappa; D017450:Receptors, Opioid, mu