Novel opioid peptide derived antagonists containing (2S)-2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid [(2S)-Mdcp].
A synthesis of the novel tyrosine analogue (2 S)-2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid [(2 S)-Mdcp] (15) was developed. In (2 S)-Mdcp, the amino and hydroxyl groups of 2',6'-dimethyltyrosine are replaced by a methyl and a carbamoyl group, respectively, and its substitution for Tyr (1) in opioid agonist peptides resulted in compounds showing antagonism at all three opioid receptors. The cyclic peptide (2 S)-Mdcp-c[D-Cys-Gly-Phe(pNO 2)-D-Cys]NH 2 (1) was a potent and selective mu antagonist, whereas (2 S)-Mdcp-c[D-Pen-Gly-Phe(pF)-Pen]-Phe-OH (3) showed subnanomolar delta antagonist activity and extraordinary delta selectivity.
Ghosh
Animesh
A
Department of Chemistry and Medicinal Chemistry Program, Office of Life Sciences, National University of Singapore, 3 Science Drive 3, Singapore.
Luo
Jie
J
Liu
Chen
C
Weltrowska
Grazyna
G
Lemieux
Carole
C
Chung
Nga N
NN
Lu
Yixin
Y
Schiller
Peter W
PW
D001549:Benzamides / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D018847:Opioid Peptides / Q000737:chemistry*; D010666:Phenylpropionates / Q000494:pharmacology*; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D021241:Spectrometry, Mass, Electrospray Ionization
C532165:2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid; D001549:Benzamides; D018847:Opioid Peptides; D010666:Phenylpropionates; D017465:Receptors, Opioid, delta
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