Replacement of the N-terminal tyrosine residue in opioid peptides with 3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid (Dcp) results in novel opioid antagonists.
3-(2,6-Dimethyl-4-carbamoylphenyl)propanoic acid (Dcp), a 2',6'-dimethyltyrosine analogue containing a carbamoyl group in place of the hydroxyl function and lacking the amino group, was synthesized. The replacement of Tyr1 in an enkephalin analogue and in dynorphin A(1-11)-NH2 with Dcp resulted in the first opioid peptide-derived antagonists that do not contain a phenolic hydroxyl group at the 1-position residue. The cyclic peptide Dcp-c[D-Cys-Gly-Phe(pNO2)-D-Cys]NH2 represents a novel, potent mu opioid antagonist.
Lu
Yixin
Y
Department of Chemistry and Medicinal Chemistry Program, Office of Life Sciences, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore. chmlyx@nus.edu.sg
Lum
Tze Keong
TK
Leow Augustine
Yoon Wui
YW
Weltrowska
Grazyna
G
Nguyen
Thi M-D
TM
Lemieux
Carole
C
Chung
Nga N
NN
Schiller
Peter W
PW
D001549:Benzamides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D015394:Molecular Structure; D009292:Narcotic Antagonists; D018847:Opioid Peptides / Q000737:chemistry* / Q000494:pharmacology*; D010666:Phenylpropionates / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000737:chemistry
C513861:3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid; D001549:Benzamides; D009292:Narcotic Antagonists; D018847:Opioid Peptides; D010666:Phenylpropionates; C076121:2',6'-dimethyltyrosine; D014443:Tyrosine