|Title||Cyclic non-opioid dynorphin A analogues for the bradykinin receptors.|
|Publication Type||Journal Article|
|Year of Publication||2016|
|Authors||Lee YSun, Remesic M, Ramos-Colon C, Hall SM, Kuzmin A, Rankin D, Porreca F, Lai J, Hruby VJ|
|Journal||Bioorg Med Chem Lett|
|Date Published||2016 Nov 15|
|Keywords||Amino 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 Journal||Bioorg. Med. Chem. Lett.|
|PubMed Central ID||PMC5159310|
|Grant List||P01 DA006284 / DA / NIDA NIH HHS / United States |
R01 DA013449 / DA / NIDA NIH HHS / United States
Cyclic non-opioid dynorphin A analogues for the bradykinin receptors.
Faculty Member Reference:
Yeon Sun Lee, Ph.D.
Frank Porreca, PhD