A natural extract of the opium poppy, morphine was, in the 19th century, the first natural substance purified to homogeneity for medical use, Manglik said.
Advertisement
Other researchers had established that morphine-resembling drugs’ analgesic effect is brought about by a particular cascade of downstream chemical reactions – also known as a molecular pathway – set in motion when these drugs bind to the mu opioid receptor, while their respiration-suppressing effect is induced by another molecular pathway tripped off by the same binding event.
Scientists have designed a promising new painkiller that appears to separate the powerful pain dulling effects of synthetic opioids from side effects that include physical dependence, constipation, and potentially fatal respiratory depression.
That wasn’t thought possible until 2000, when a scientist named Laura Bohn found out something about a protein called beta-arrestin, which sticks to the opioid receptor when something like morphine activates it.
What if you could design a drug that has all the pain-relieving power of morphine but none of its risky or addictive side effects?
The big-data methods used by the researchers also open up a promising avenue in drug innovation, they reported in the journal Nature. At certain dosages, they had less withdrawal. In stark contrast with morphine, though, it had no discernable effect on the mice’s breathing.
Other experiments performed in the Stanford laboratory of Gregory Scherrer, PhD, assistant professor of anesthesiology, perioperative and pain medicine and of neurosurgery, showed that PZM21 had no effect on mice bioengineered to lack the mu opioid receptor, confirming the compound’s mechanism of action. Now it seems they could be untied.
“We’re cautiously optimistic”, said Aashish Manglik, an instructor in molecular and cellular physiology at Stanford University’s School of Medicine and one of the study’s main authors.
After Bohn’s discovery, a number of people, including a team that includes Manglik, started looking for a drug that could connect to the mu-opioid receptor in a way that avoids the negative effects of beta-arrestin.
Shoichet and his colleagues took advantage of computer modeling to test more than 3 million known chemicals against the structure of human cell receptors that are activated by morphine.
So unlike opiates, the new medicine might not trigger a surge in dopamine, a brain chemical involved in emotions like addiction, pleasure and pain, said Brian Shoichet, senior author of a paper on the new drug published on Wednesday in Nature.
Most such efforts have tried to tweak the drug’s chemical structure to get rid of the side-effects.
A collaborative team of researchers have identified a new compound which appears to have similar painkilling properties as morphine but without its potentially lethal side effects – notably, the suppression of the respiratory system.
In the tests with mice, the higher the dose of PZM21, the more pain relief they felt.
“If you give a mouse a drug that activates its reward pathways like cocaine, amphetamine or morphine, the mice just run around more”.
Using computer modelling, Manglik, in collaboration with other scientists across the various institutions, screened 2,500 compounds in a “virtual medicinal-compound cabinet” to see which compounds could bind to the μ-opioid receptor. Given a choice between two chambers, one paired to an injection of a solution containing PZM21 and the other to an otherwise identical solution that lacked PZM21, the mice showed no preference for either chamber. Like morphine and other opioids, PZM21 caused mice to slow their breathing to dangerously low levels. It would be eerily convenient if only the negative effects of opiates are tied to this one protein. “The real experiment for a lot of these things is going to have to happen in humans”, he said, adding that addiction is “really a human disease”.
“I think this was really a tour de force”, says Gavril Pasternak, a researcher at the Memorial Sloan Kettering Cancer Center who’s also trying to develop new opioids but was not involved in this study. “These are great promise for opiates over the course of the next five to 10 years”. Both results distinguished the new compound from other painkillers and from Oliceridine, a comparable molecule developed by Trevena, Inc. that’s in clinical trials, Manglik said.
Advertisement
A drug with these characteristics would come as good news to physicians, patients and public-health authorities deeply concerned about a growing epidemic of addictive-painkiller abuse. “We have some really gorgeous compounds, and I think opiates are a awful epidemic”.
