Synthesis of stable and potent δ/μ opioid peptides: Analogues of H-Tyr-c[D-Cys-Gly-Phe-D-Cys]-OH by ring-closing metathesis

Adriano Mollica, Giovanni Guardiani, Peg Davis, Shou Wu Ma, Frank Porreca, Josephine Lai, Luisa Mannina, Anatoli P. Sobolev, Victor J. Hruby

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

Ring-closing metathesis has emerged as a powerful tool in organic synthesis for generating cyclic structures via C-C double bond formation. Recently, it has been successfully used in peptide chemistry for obtaining cyclic molecules bridged through an olefin unit in place of the usual disulfide bond. Here, we describe this approach for obtaining cyclic olefin bridged analogues of H-Tyr-c[D-Cys-Gly-Phe-Cys]-OH. The synthesis of the new ligands was performed using the second generation Grubbs' catalyst. The resulting cis-8 (cDADAE) and trans-9 (tDADAE) were fully characterized and tested at δ, μ, and κ opioid receptors. Also the linear precursor 13 (lDADAE) and the hydrogenated derivative 11 (rDADAE) also were tested. All the cyclic products containing a olefmic bond are slightly selective but highly active and potent for the δ and μ opioid receptors. Activity toward the κ opioid receptors was absent or very low.

Original languageEnglish (US)
Pages (from-to)3138-3142
Number of pages5
JournalJournal of Medicinal Chemistry
Volume50
Issue number13
DOIs
StatePublished - Jun 28 2007

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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