Synthesis of bicyclic dipeptide mimetics for the cholecystokinin and opioid receptors

John M. Ndungu, Xuyuan Gu, Dustin E. Gross, James P. Cain, Michael D. Carducci, Victor J. Hruby

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The cholecystokinin C-terminal octapeptide analogue H-Asp-Tyr-D-Phe-Gly- Trp-(N-Me)-Nle-Asp-Phe-NH2 (SNF 9007) is a potent and selective ligand for both the CCK-B and δ-opioid receptors. To constrain the peptide into the biologically active conformation(s), bicyclic dipeptide mimetics for Nle-Gly and homoPhe-Gly were designed and synthesized from β-substituted aspartic acids. Alkylation of L-aspartic acid using lithium bis(trimethylsilyl) amide (LHMDS) in the presence of hexamethylphosphoramide (HMPA) gave β-substituted aspartic acids, with the major product being the (2S,3R) isomer. Additional isomers of Nle-Gly bicyclic dipeptide mimetic were obtained via the Kazmaier-Claisen rearrangement reaction. The stereochemistries of the bicyclic dipeptide mimetics were assigned by X-ray and NMR.

Original languageEnglish (US)
Pages (from-to)4139-4142
Number of pages4
JournalTetrahedron Letters
Volume45
Issue number21
DOIs
StatePublished - May 17 2004

Keywords

  • Bicyclic dipeptide
  • Cholecystokinin
  • Constrained peptides
  • Kazmaier-Claisen rearrangement
  • β-Substituted aspartic acid

ASJC Scopus subject areas

  • Biochemistry
  • Drug Discovery
  • Organic Chemistry

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