Abstract
‘Biased’ ligands of G protein-coupled receptors (GPCRs) represent a type of promising analgesic with reduced on-target side effects. PZM21, a potent μ-opioid-receptor (μOR)-biased agonist with a new chemical scaffold compared to classic opioids, has been identified as a therapeutic lead molecule for treating pain. In the current study, novel PZM21 analogues were synthesized and evaluated for their in vitro and in vivo efficacy. Novel compound 7a and PZM21 demonstrated undetectable β-arrestin-2 recruitment, however, their analgesic effects need to be further confirmed. Compounds 7b, 7d, and 7g were stronger analgesics than PZM21 in both the mouse formalin injection assay and the writhing test. Compound 7d was the most potent analogue, requiring a dose that was 1/16th to 1/4th of that of PZM21 for its analgesic activity in the two assays, respectively. Therefore, compound 7d could serve as a lead to develop new biased μOR agonists for treating pain.
Highlights
The discovery of safer and more effective analgesics without the drawbacks of classic opioids is urgently needed
‘Biased’ ligands of G protein-coupled receptors (GPCRs) represent a type of promising molecule with a specific ability to cherry pick the beneficial rather than the deleterious signaling pathways activated by the μ-opioid-receptor so that on-target toxicity is reduced [1,2,3]
Previous research has shown that opioid-induced analgesia results from μOR signaling through the G protein Gi ; while many side effects, including respiratory depression and constipation, may be transmitted through β-arrestin pathway signaling, which occurs downstream of μOR activation [9,10,11]
Summary
The discovery of safer and more effective analgesics without the drawbacks of classic opioids is urgently needed. Recent studies have suggested that some GPCR ligands exhibit an “unbalanced effect” when activating signaling pathways They can bind to specific receptor forms [4,5] or selectively bind to different types of G protein subunits or even β-arrestin, thereby biasing the cytoplasmic signal to a certain pathway. PZM21 (Figure 1) is a potent biased μOR agonist with a structurally distinct chemical scaffold unrelated to known opioids. It was initially identified from over three million molecules by computational docking against the μOR structure; it is a promising therapeutic lead for pain.
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