A morphine alternative with less overdose risk?300 views
The big-data methods used by the researchers also open up a promising avenue in drug innovation, they reported in the journal Nature.
In a collaborative study, scientists at multiple USA universities found the drug candidate PZM21, which was tested in mice, resembles morphine and other drugs like it, but may be less addictive.
In addition to morphine, these opioids include the prescription painkillers codeine, oxycodone, oxycontin, hydrocodone and fentanyl as well as illicit drugs such as heroin.
Respiratory suppression caused by opioids results in some 30,000 deaths every year in the United States alone, where opioid use and abuse has taken on epidemic proportions.
When given a choice between two chambers, one paired to an injection of a solution spiked with PZM21 and the other to the solution without it, the mice showed no preference for either chamber. PZM21, the researchers summed up, offers “long-lasting analgesia coupled to apparent elimination of respiratory depression”.
Opium and its derivatives have been used to boring pain (and generate euphoric feelings) for more than 4,000 years. “But it is obviously unsafe too”, said Brian Shoichet, a professor at the University of California’s School of Pharmacy in San Francisco, and one of three senior authors of the study.
The researchers created this compound by studying the structure of opioid receptors themselves. Most such efforts have tried to tweak the drug’s chemical structure to get rid of the side-effects.
Today (August 17), scientists from several institutions including Stanford University Medical School and the University of North Carolina at Chapel Hill Medical School revealed that they have identified a compound that appears to work as a painkiller similar to morphine, but without the same affinity for addiction.
Understanding how the receptor interacts with morphine or other drugs let the PZM21 developers replicate morphine’s benefits without setting off chemical reactions that suppress breathing.
But to avoid addiction and respiratory failure, that same molecule must not, as does morphine, dock with a second receptor that provokes those unwanted reactions.
Kobilka credits fellow researcher Brian Shoichet with figuring out that step: “His approach was, if you want to find something that behaves differently, you have to find something that looks different from other drugs”.
“But when you start with the structure of the receptor you want to target, you can throw all those constraints away”. With that information in hand, researchers were able to screen about 3 million compounds, using 4 trillion virtual simulations, to see which ones produced the right interaction with the mu opioid receptor.
After eliminating those resembling opioids too closely, only 23 remained. Study author Dr. Bryan Roth, Ph.D., pharmacology professor and medicinal chemistry at UNC, analyzed the candidates further and identified one that strongly activated the “good” pathway without the “bad” one, according to the release.
Even then, more custom-engineering was required. In a commentary accompanying the report, McGill University researcher Brigitte Kieffer, who was not involved in the research, wrote that the pain relieving effects “supersede the adverse effects classically observed for morphine”.
The new research, she added, was “a step toward the ideal drug”. “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.
More tests in animals need to explore whether this compound, known for now as PZM21, is safe and effective before it could move to human trials, said Shoichet.
Courtesy: The Villages Sun Times