Cyclic non-opioid dynorphin A analogues for the bradykinin receptors. Issue 22 (15th November 2016) - Lee, Yeon Sun
Graphical abstract: 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 ligands1 and4, along with the key structural feature (i.e. amphipathicity) for the BRs. However, the ligands showed very low metabolic stability in plasma ( t 1/2 <1 h) and therefore, in order to improve their metabolic stabilities with retained biological activities, various modifications were performed. Cyclization of ligand4 afforded a cyclic Dyn A analogue5 that retained the same range of binding affinity as the linear ligand with improved metabolic stability ( t 1/2 >5 h) and therefore possesses the potential as a pharmacophoric scaffold to be utilized for drug development.