Cyclic non-opioid dynorphin A analogues for the bradykinin receptors

Yeon Sun Lee, Michael Remesic, Cyf Ramos-Colon, Sara M. Hall, Alexander Kuzmin, David Rankin, Frank Porreca, Josephine Lai, Victor J. Hruby

Research output: Contribution to journalArticlepeer-review

6 Scopus citations


Nerve injury and inflammation cause up-regulation of an endogenous opioid ligand, dynorphin A (Dyn A), in the spinal cord resulting in hyperalgesia via the interaction with bradykinin receptors (BRs). This is a non-opioid neuroexcitatory effect that cannot be blocked by opioid antagonists. Our systematic structure–activity relationships study on Dyn A identified lead ligands 1 and 4, along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma (t1/2<1 h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed. Cyclization of ligand 4 afforded a cyclic Dyn A analogue 5 that retained the same range of binding affinity as the linear ligand with improved metabolic stability (t1/2>5 h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development.

Original languageEnglish (US)
Pages (from-to)5513-5516
Number of pages4
JournalBioorganic and Medicinal Chemistry Letters
Issue number22
StatePublished - 2016


  • Amphipathicity
  • Bradykinin receptors
  • Cyclic ligands
  • Metabolic stability
  • Non-opioid dynorphin A
  • Structure–activity relationship

ASJC Scopus subject areas

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


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