Cyclic opioid peptide agonists and antagonists obtained via ring-closing metathesis.
The opioid peptide H-Tyr-c[D-Cys-Phe-Phe-Cys]NH(2) cyclized via a methylene dithiother is a potent and selective mu opioid agonist (Przydial M.J. et al., J Peptide Res, 66, 2005, 255). Dicarba analogues of this peptide with Tyr, 2',6'-dimethyltyrosine (Dmt), 3-[2,6-dimethyl-4-hydroxyphenyl)propanoic acid (Dhp) or (2S)-2-methyl-3-(2,6-dimethyl-4-hydroxyphenyl)propanoic acid [(2S)-Mdp] in the 1-position were prepared. The peptides were synthesized on solid-phase by substituting d-allylglycine and (2S)-2-amino-5-hexenoic acid in position 2 and 5, respectively, followed by ring-closing metathesis. Mixtures of cis and trans isomers of the resulting olefinic peptides were obtained, and catalytic hydrogenation yielded the saturated -CH(2)-CH(2)- bridged peptides. All six Tyr(1)- and Dmt(1)-dicarba analogues retained high mu and delta opioid agonist potency and showed only slight or no preference for mu over delta receptors. As expected, the six Dhp(1)- and (2S)-Mdp(1)-dicarba analogues turned out to be mu opioid antagonists but, surprisingly, displayed a range of different efficacies (agonism, partial agonism or antagonism) at the delta receptor. The obtained results indicate that the mu versus delta receptor selectivity and the efficacy at the delta receptor of these cyclic peptides depend on distinct conformational characteristics of the 15-membered peptide ring structure, which may affect the spatial positioning of the exocyclic residue and of the Phe(3) and Phe(4) side chains.
Berezowska
Irena
I
Laboratory of Chemical Biology and Peptide Research, Clinical Research Institute of Montreal, Montreal, QC, Canada H2W 1R7.
Lemieux
Carole
C
Chung
Nga N
NN
Wilkes
Brian C
BC
Schiller
Peter W
PW
D000595:Amino Acid Sequence; D000701:Analgesics, Opioid / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018847:Opioid Peptides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D017465:Receptors, Opioid, delta / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000037:antagonists & inhibitors* / Q000378:metabolism
D000701:Analgesics, Opioid; D018847:Opioid Peptides; D010456:Peptides, Cyclic; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu
Br J Pharmacol. 1972 Dec;46(4):764-6
4655272
J Med Chem. 1987 Nov;30(11):2094-9
2822930
Br J Pharmacol Chemother. 1957 Mar;12(1):119-27
13413163
Proc Natl Acad Sci U S A. 1983 Oct;80(19):5871-4
6310598
Biochem Pharmacol. 1973 Dec 1;22(23):3099-108
4202581
J Pept Res. 2005 Nov;66(5):255-62
16218993
J Med Chem. 1992 Feb 21;35(4):684-7
1311764
J Med Chem. 1982 Dec;25(12):1432-8
6296388
Life Sci. 1988;43(12):1013-20
2845204
Biochem Biophys Res Commun. 1978 Dec 29;85(4):1332-8
217386
Biochem Biophys Res Commun. 1981 Jul 30;101(2):337-43
6272756
J Med Chem. 2001 Sep 13;44(19):3048-53
11543672
J Med Chem. 1989 Mar;32(3):698-703
2537427
Biopolymers. 2005;80(2-3):325-31
15614807
Org Lett. 2003 Jan 9;5(1):47-9
12509887
Helv Chim Acta. 1974;57(5):1253-9
4854571
J Med Chem. 2007 Jun 28;50(13):3138-42
17539621
Eur J Pharmacol. 1979 Sep 1;58(1):11-8
499333
Acta Biochim Pol. 2006;53(1):73-6
16496038
Org Lett. 1999 Sep 23;1(6):953-6
10823227
Br J Pharmacol Chemother. 1968 Jun;33(2):266-76
5664147
J Med Chem. 2007 Mar 22;50(6):1414-7
17315860