title: Novel opioid peptide derived antagonists containing (2S)-2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid [(2S)-Mdcp].
abstract: 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.
authors.affiliation: Department of Chemistry and Medicinal Chemistry Program, Office of Life Sciences, National University of Singapore, 3 Science Drive 3, Singapore.
authors.forename: Animesh
authors.initials: A
authors.lastname: Ghosh
authors.forename: Jie
authors.initials: J
authors.lastname: Luo
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Grazyna
authors.initials: G
authors.lastname: Weltrowska
authors.forename: Carole
authors.initials: C
authors.lastname: Lemieux
authors.forename: Nga N
authors.initials: NN
authors.lastname: Chung
authors.forename: Yixin
authors.initials: Y
authors.lastname: Lu
authors.forename: Peter W
authors.initials: PW
authors.lastname: Schiller
mesh_terms: 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
chemical_list: C532165:2-methyl-3-(2,6-dimethyl-4-carbamoylphenyl)propanoic acid; D001549:Benzamides; D018847:Opioid Peptides; D010666:Phenylpropionates; D017465:Receptors, Opioid, delta
references.citation: Biopolymers. 1999;51(6):411-25
references.pmid: 10797230
references.citation: J Med Chem. 2001 Sep 13;44(19):3048-53
references.pmid: 11543672
references.citation: Life Sci. 2003 Jun 27;73(6):691-8
references.pmid: 12801590
references.citation: J Med Chem. 2004 Jan 29;47(3):612-26
references.pmid: 14736242
references.citation: Bioorg Med Chem Lett. 2004 Jul 5;14(13):3545-8
references.pmid: 15177470
references.citation: Life Sci. 1983;33 Suppl 1:319-22
references.pmid: 6319885
references.citation: Bioorg Med Chem Lett. 2008 Feb 15;18(4):1350-3
references.pmid: 18207400
references.citation: J Med Chem. 1990 Jun;33(6):1714-20
references.pmid: 2160538
references.citation: J Med Chem. 1992 Feb 21;35(4):684-7
references.pmid: 1311764
references.citation: J Med Chem. 1997 Nov 21;40(24):3957-62
references.pmid: 9397176
references.citation: J Pept Res. 2005 Jan;65(1):36-41
references.pmid: 15686532
references.citation: J Med Chem. 2006 Aug 24;49(17):5382-5
references.pmid: 16913729
references.citation: J Med Chem. 2007 Feb 8;50(3):512-20
references.pmid: 17266203
references.citation: J Med Chem. 1986 Nov;29(11):2370-5
references.pmid: 2878079