Structure-Activity Relationships of the Peptide Kappa Opioid Receptor Antagonist Zyklophin

Anand A. Joshi, Thomas F. Murray, Jane V. Aldrich

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8 Scopus citations


The dynorphin (Dyn) A analogue zyklophin ([N-benzyl-Tyr1-cyclo(d-Asp5,Dap8)]dynorphin A(1-11)NH2) is a kappa opioid receptor (KOR)-selective antagonist in vitro, is active in vivo, and antagonizes KOR in the CNS after systemic administration. Hence, we synthesized zyklophin analogues to explore the structure-activity relationships of this peptide. The synthesis of selected analogues required modification to introduce the N-terminal amino acid due to poor solubility and/or to avoid epimerization of this residue. Among the N-terminal modifications, the N-phenethyl and N-cyclopropylmethyl substitutions resulted in analogues with the highest KOR affinities. Pharmacological results for the alanine-substituted analogues indicated that Phe4 and Arg6, but interestingly not the Tyr1 phenol, are important for zyklophin's KOR affinity and that Arg7 was important for KOR antagonist activity. In the GTPγS assay, while all of the cyclic analogues exhibited negligible KOR efficacy, the N-cyclopropylmethyl-Tyr1 and N-benzyl-Phe1 analogues were 28- and 11-fold more potent KOR antagonists, respectively, than zyklophin.

Original languageEnglish (US)
Pages (from-to)8783-8795
Number of pages13
JournalJournal of Medicinal Chemistry
Issue number22
StatePublished - Nov 25 2015

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery


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