A new compound has been developed by researchers using advanced computational techniques that can block pain effectively without the dangerous side effects of current prescription painkillers.
Morphine, without the risk
Morphine is a crucial medicinal tool that provides effective pain relief for a wide range of applications. However, the alkaloid from the opium poppy also poses a number of serious life threatening side effects. Aiming to eliminate the deadly risks of morphine, an international research team has developed a novel drug candidate based on the recently deciphered atomic structure of the ‘morphine receptor’ in the brain.
In a new study published in Nature, the team led by scientists at UC San Francisco, Stanford University, the University of North Carolina, and the Friedrich-Alexander University Erlangen-Nürnberg custom-engineered a new drug that blocked pain as effectively as morphine in mouse experiments. Importantly though, the drug did not bring with it the same potentially lethal side effects. In particular, it did not affect breathing – the most common cause of death from morphine overdose.
The new drug also did not cause drug-seeking behaviour in mice. Morphine’s highly addictive nature, driven by dopamine circuitry in the brain, is another serious problem that often leads to abuse and withdrawal symptoms when the dose is reduced. Opioids are particularly dangerous with the World Health Organisation estimating that 69,000 people die worldwide from opioid overdose. The new drug could transform the fight against this epidemic. However, the authors of the study say more work is needed to find out if the compound is truly non-addictive and to confirm that it is as safe and effective in humans as it is in rodents.
Twisting and turning trillions of times
Normally new drugs are discovered by adapting an already successful drug like morphine to reduce unwanted side effects. But the researchers in this new study took a radically different approach. “We didn’t want to just optimize chemistry that already existed, we wanted to get new chemistry that would confer completely new biology,” said Brian Shiochet, professor of pharmaceutical chemistry at UCSF and co-senior author of the paper.
To be able to take this powerful new approach depended heavily on knowing the atomic structure of the brain’s ‘morphine receptor’. This has been recently figured out by Nobel laureate and co-senior author Brian Kobilka, a professor of molecular and cellular physiology at the Stanford University School of Medicine. Using this structural model, Shiochet’s team were able to apply a computational method known as ‘molecular docking’. Over two weeks the researchers performed around 4 trillion ‘virtual experiments’, simulating how millions of different candidate drugs could turn and twist in millions of different angles. The goal being to find the best configurations to fit the receptor and activate it, creating the same effects as morphine.
Once a list of 23 candidate drugs had been developed, real world trials began with the aim of finding the most potent of them. The resulting molecule was named PZM21 and is chemically unrelated to existing opioid drugs. In pharmacological tests PZM21 efficiently blocked pain without producing constipation and breathing suppression as traditional opioids do. The drug also appeared to dull pain by affecting opioid circuits in the brain only, with little effect on opioid receptors in the spinal cord, Shiochet said, calling it “unprecedented, weird and cool.”