Des-Arg~7-Dynorphin A Analogs for Brady kinin-2 Receptor

摘要

Under chronic pain and inflammation, dynorphin A (Dyn A) (Figure 1) is up-regulated in the spinal cord and up-regulated Dyn A interacts with bradykinin-2 receptor (B2R) resulting in hyperalgesia [1,2]. Since there is no evidence for de novo synthesis of the endogenous ligand, bradykinin (BK) or its precursors in the spinal cord, it supports the fact that activation of spinal B2R promotes pain, and that they are activated by upregulated Dyn A. This is a non-opioid effect that cannot be blocked by opioid antagonists. On the basis of this fact, we have been developing Dyn A-based ligands to block the hyperalgesic effect of B2R in the spinal cord. Our systematic structure-activity relationships (SAR) study identified a good pharmacophore of Dyn A for the central B2R: amphipathic non-opioid fragment, Dyn A-(4-11), and also validated that the truncation of Arg residue in all Dyn A fragments does not affect their respective binding affinity at the receptor (Figure 1, Table 1).