Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives

Srinivas Deekonda, Lauren Wugalter, David Rankin, Tally M. Largent-Milnes, Peg Davis, Yue Wang, Neemah M. Bassirirad, Josephine Lai, Vinod Kulkarni, Todd W. Vanderah, Frank Porreca, Victor J. Hruby

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at μ and δ opioid receptors. They exhibit very good affinities at μ and δ opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at μ and δ opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 ± 5.9 nM) and GPI (4.6 ± 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (<15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required.

Original languageEnglish (US)
Pages (from-to)4683-4688
Number of pages6
JournalBioorganic and Medicinal Chemistry Letters
Volume25
Issue number20
DOIs
StatePublished - Oct 15 2015

Keywords

  • Bivalent ligands
  • Enkephalins
  • Opioid receptors
  • Opioids

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

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