Cyclic non-opioid dynorphin A analogues for the bradykinin receptors.

Abstract

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 <1h) 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 >5h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development.

• Authors: Yeon Sun Lee, Michael Remesic, Cyf Ramos-Colon, Sara M Hall, Alexander Kuzmin, David Rankin, Frank Porreca, Josephine Lai, Victor J Hruby
• Journal: Bioorganic & medicinal chemistry letters (Bioorg Med Chem Lett) Vol. 26 Issue 22 Pg. 5513-5516 (11 15 2016) ISSN: 1464-3405 [Electronic] England
• PMID: 27756562 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, U.S. Gov't, P.H.S.)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Analgesics, Non-Narcotic
• Bradykinin Receptor Antagonists
• Ligands
• Receptors, Bradykinin
• Dynorphins

Topics

• Amino Acid Sequence
• Analgesics, Non-Narcotic (chemistry, pharmacology)
• Animals
• Bradykinin Receptor Antagonists (chemistry, pharmacology)
• Cyclization
• Dynorphins (chemistry, pharmacology)
• Ligands
• Rats
• Receptors, Bradykinin (metabolism)
• Structure-Activity Relationship