In a study published in the journal Nature, researchers reveal how they deciphered the atomic structure of the “morphine receptor” in the brain to create a drug compound that blocks pain just as well as morphine, but without the harmful side effects that can lead to patient death.
What is more, the team says – unlike current opioids – the compound does not activate the brain’s reward region, so it has the potential to reduce addiction.
Creating a new opioid from scratch
Despite the harms associated with opioids, there is no doubt the drugs offer significant benefits for many patients with moderate to severe pain.
In an unusual departure from the “party line” that opioids aren’t good for chronic pain, these researchers actually admit how effective opioids are.
Though they do not specifically mention to chronic pain, their beneficent view of opioids could be because they are getting ready to sell another drug from this class.
“Morphine transformed medicine,” notes co-senior author Brian Shoichet, Ph.D., a professor of pharmaceutical chemistry in the School of Pharmacy at the University of California-San Francisco (UCSF).
Rather than trying to change the structure of morphine, the researchers of the new study looked at how they could develop a new opioid from scratch by using information about the structure of the brain’s morphine receptor – the mu-opioid receptor.
PZM21 caused no respiratory problems, constipation in mice
For their study, the researchers combined the structural information of the mu-opioid receptor with a computational technique called “molecular docking.”
This allowed the team to conduct around 4 trillion “virtual experiments,” simulating how more than 3 million molecules might fit to the structure of the mu-opioid receptor and activate it.
Specifically, the researchers searched for molecules that bind to the receptor and activate G-protein signaling to reduce pain perception, but that do not activate beta-arrestin2 – a protein that is responsible for respiratory problems and constipation associated with opioid use.
The researchers pinpointed 23 molecules that showed promise, and by increasing the chemical efficacy of these molecules 1000-fold, they found the most effective candidate was once they call PZM21.
Next, the researchers tested PZM21 in lab experiments and mouse models. They found the molecule was able to target the mu-opioid receptor to reduce pain signaling just as effectively as morphine, but it did not trigger breathing problems and constipation.
They also found the molecule primarily targeted opioid circuits in the brain to relieve pain, with little impact on the opioid receptors in the spinal cord. According to the team, no other opioid has such specificity.
“We haven’t shown this is truly non-addictive,” notes Shoichet. “At this point we’ve just shown that mice don’t appear motivated to seek out the drug.”