Agent kills pain like morphine but loses some side effects | August 22, 2016 Issue - Vol. 94 Issue 33 | Chemical & Engineering News
Volume 94 Issue 33 | News of The Week
Issue Date: August 22, 2016 | Web Date: August 19, 2016

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
Department: Science & Technology
News Channels: Biological SCENE
Keywords: drug discovery, morphine, µ-opioid receptor, pain relief, side effects
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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.
Credit: Adapted from Nature
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.
 
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.
Credit: Adapted from Nature

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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Comments
Vance Frickey (August 17, 2016 7:05 PM)
What'll be interesting is if the "reflexive" response of the US Drug Enforcement Administration to anything they consider "abuse" of a pain-relieving drug is triggered by oliceridine or PAM21. Lately, what the DEA's been chasing isn't actually the properties of opioid agonists, but the ingenuity of some recreational drug abusers in misusing any compound, licit or illicit, in pursuit of a "high".

I've been fighting neuroendocrine cancer since 1998. A good selective opioid agonist which avoids respiratory depression and constipation would be a godsend to those of us whose cancers cause pain from invasion of nerves and highly-innervated tissue by tumors. One can hope that the Drug Abuser-DEA Complex can be induced to leave these new opioid agonists alone so cancer and other chronic pain sufferers can be treated appropriately for their pain.
Keiland Cooper (August 21, 2016 3:38 PM)
This could be useful in heroin overdose treatments as well as respiratory arrest is the leading cause of death from OD.
TB (August 25, 2016 10:52 AM)
Why are we messing with opiates? They are the biggest problem for Americans. Let's free the weed and see how many reach for opiates. The pharmaceutical industry is going to go bye bye. So see ya! Melinnials are here!

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