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Aug242016

Scientists use structural modeling to identify novel opioid analgesics with fewer side effects

Current treatments for chronic pain center on µ-opioid analgesics, such as morphine and oxycodone. These drugs are highly addictive and can fatally depress respiration. The need for new classes of analgesics has been recognized since the 19th century1; however µ-opioid analgesics are still a standard of care in spite of their side effects. As 50 million Americans currently suffer from chronic pain2, innovative treatment options are critical for improved pain management.

A recent study published in Nature by Manglik, Lin, and Aryal et al. 1 used computational  modeling to identify a structurally novel µ-opioid agonist that propagates receptor signaling through the downstream Gi protein (to produce analgesic effects), but does not recruit the downstream β-arrestin-2 protein (thus avoiding certain side effects). To accomplish this, the authors computationally screened over 3 million compounds and rigorously optimized and validated the top hits using additional structural modeling, in vitro opioid receptor binding assays, Gi protein signaling assays, and β-arrestin-2 recruitment assays. PZM21 was identified as a highly selective and potent µ-opiate receptor agonist, which importantly did not show off target effects for hERG or neurotransmitter transporters.

To take the next steps, the authors demonstrated that short-term PZM21 treatment was analgesic and safe in rodents through in vivo behavioral assays. Interestingly, PZM21 produced CNS-specific analgesia in mice, while morphine produced both CNS- and spinal-mediated analgesia. PZM21 was longer-acting and showed fewer side effects than morphine. Importantly, respiratory depression was not observed with PZM21 treatment. Finally, the authors explored the addictive potential of PZM21 in mice. Encouragingly, in hyper-locomotion and conditioned place preference paradigms, PZM21 did not significantly activate dopamine reward circuitry, and thus did not show addictive properties.

I believe this rigorous study creatively bridges computational biology, in vitro biochemistry, and in vivo efficacy models to identify novel alternatives to current analgesics. However, more work is needed to translate PZM21-like molecules to humans. Beyond standard toxicity and dose-finding requirements, I think it will be important to perform addiction studies with extended dosing paradigms past the ten-day window examined here, as chronic pain patients require long-term treatment. Further, as PZM21 is structurally unique from morphine, and therefore may have a different mechanism of action, I think it will be important to assess whether naloxone can reverse PZM21 toxicity for emergency situations.

-TMG

1) Aashish Manglik*, Henry Lin*, Dipendra K. Aryal*, John D. McCorvy,    Daniela Dengler, Gregory Corder, Anat Levit, Ralf C. Kling, Viachaslau Bernat, Harald Hübner, Xi-Ping Huang, Maria F. Sassano, Patrick M. Giguère, Stefan Löber, Da Duan, Grégory Scherrer, Brian K. Kobilka, Peter Gmeiner, Bryan L. Roth & Brian K. Shoichet. Structure-based discovery of opioid analgesics with reduced side effects Nature 1–6 (2016) doi:10.1038/nature19112

2) NIH Study Shows Prevalence of Chronic or Severe Pain in U.S. Adults. 2016. http://americanpainsociety.org/about-us/press-room/nih-study-shows-prevalence-of-chronic-or-severe-pain-in-u-s-adults

Image taken from article http://www.foxnews.com/health/2016/08/17/new-opioid-candidate-may-help-reduce-overdoses.html

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