Manglik et al. [1] , writing in Nature, believe they may have found a new form of painkiller that works just as well as morphine but lacks its potentially lethal side effect. The authors have found it is not addictive by discovering a biased agonist that selectively targets the G-protein pathway over β-arrestin. Binding of agonists, such as morphine, to the μ-opioid-receptor cause very powerful reductions in the sensation of pain or analgesia via the G-protein signalling pathway but has the major side-effect of respiratory depression (the major cause of death in heroin addicts) and constipation. A further unwanted side effect limiting the use of morphine is addiction by activating the dopaminergic reward circuits. The authors show the new μ-opioid agonist PZM21 selectively activates the G-protein signalling pathway to give the desired analgesia in animal models but does not activate β-arrestin pathway, so causes little respiratory depression or constipation nor alters the dopamine pathway so would be predicted not to be addictive.
The research is important as the authors report PZM21 in mice was comparable to morphine but longer lasting. Interestingly PZM21 reduced pain in the CNS but not spinal cord in mouse models.
A biased opioid agonist TRV130 is now in Phase III trials by the company Trevena Inc that is structurally unrelated to PZM21 but has a similar pharmacological profile. Taken together, the two compounds suggest that agonists biased to the Gi/o-pathway (rather than possible differences in other pharmacological properties such as pharmacokinetics) represent a new strategy for pain control.
[1] Manglik A. et al. (2016). Structure-based discovery of opioid analgesics with reduced side effects. Nature. doi:10.1038/nature19112 advance online publication: 1-6.
Comments by Anthony Davenport
n.b. the two relevant ligands curated into GtoPdb are show below. As a new entry 9286 PZM21 will go live in release 2106.4 (September) but TRV130 was already captured as ligand 7334
guidetopharmacology blog 
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