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Drug Discovery

Agent kills pain like morphine but loses some side effects

Researchers find molecule that turns on opioid pain-relief pathway but skips one associated with constipation and respiratory distress

by Stu Borman
August 19, 2016 | A version of this story appeared in Volume 94, Issue 33

Graphic shows how binding of morphine to the µ-opioid receptor activates two pathways, relieving pain and causing respiratory and constipation side effects. PZM21 binds differently and kills pain without causing the side effects.
Credit: Adapted from Nature
When morphine binds to the µ-opioid receptor, it activates two pathways, relieving pain and causing side effects. PZM21 binds differently and kills pain without causing the side effects.

A new drug candidate, when tested in mice, can kill pain like morphine and other opioids without causing some of those drugs’ serious side effects.

Along with providing powerful pain relief, opioids also are addictive, can cause constipation, and can cause irregular breathing or even halt it. Opioids hit the µ-opioid receptor on neuron surfaces. Binding that receptor triggers two cellular processes simultaneously: a G-protein signaling pathway that causes analgesia and a β-arrestin pathway that leads to constipation and respiratory depression.

A collaborative team has now used structure-based computational drug design to find a compound that can trigger the µ-opioid receptor’s desirable G-protein signaling while avoiding its β-arrestin signaling (Nature 2016, DOI: 10.1038/nature19112). The team was led by Brian K. Kobilka of Stanford University School of Medicine, Peter Gmeiner of Friedrich Alexander University of Erlangen-Nuremberg, Bryan L. Roth of the University of North Carolina School of Medicine, and Brian K. Shoichet of the University of California, San Francisco.

Using computational docking, the researchers analyzed the interactions between a µ-opioid receptor crystal structure determined by Kobilka’s lab in 2012 and over three million molecules from ZINC, a database of compounds likely to hit biological targets. The study focused on compounds with structures distinct from those of existing opioids to make it more likely the molecules would bind the receptor differently and thus activate the pain-reduction pathway but not the β-arrestin one. Through computational screening and assays in cells, they found one such molecule. The researchers then tested numerous analogs of it computationally and in cells to find one with the best activity.

PZM21, the compound that emerged, reduces pain in mice for a longer time than morphine does but does not interfere with breathing or cause constipation.

Researchers at Trevena in King of Prussia, Pa., previously discovered oliceridine, which also kills pain while avoiding opioid side effects. The compound is now in Phase III clinical trials.

However, PZM21 causes a more specific type of pain reduction. It lowers consciously perceived “affective” pain controlled by brain neurons, whereas opioids and oliceridine reduce both affective pain and “reflexive” pain responses controlled at the spinal cord level. Whether PZM21 and oliceridine cause less dependence than opioids remains to be seen.

Jonathan Violin, scientific cofounder of Trevena, says the new study confirms the importance of structure-based drug discovery and supports the idea that biased ligands—drugs that activate one signaling pathway but not another—can lead to improved biological responses.

The paper’s four corresponding authors and lead author Aashish Manglik of Stanford have cofounded a company called Epiodyne to develop PZM21-like analgesics.

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