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

TitleCyclic non-opioid dynorphin A analogues for the bradykinin receptors.
Publication TypeJournal Article
Year of Publication2016
AuthorsLee YSun, Remesic M, Ramos-Colon C, Hall SM, Kuzmin A, Rankin D, Porreca F, Lai J, Hruby VJ
JournalBioorg Med Chem Lett
Date Published2016 Nov 15
KeywordsAmino Acid Sequence, Analgesics, Non-Narcotic, Animals, Bradykinin Receptor Antagonists, Cyclization, Dynorphins, Ligands, Rats, Receptors, Bradykinin, Structure-Activity Relationship

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.

Alternate JournalBioorg. Med. Chem. Lett.
PubMed ID27756562
PubMed Central IDPMC5159310
Grant ListP01 DA006284 / DA / NIDA NIH HHS / United States
R01 DA013449 / DA / NIDA NIH HHS / United States
Faculty Member Reference: 
Frank Porreca, PhD