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.
While the compound's potential has only been seen in studies conducted on mice, the indications are that it may be less addictive than morphine and related drugs. When the mice were exposed to a solution containing the compound and a control solution devoid of it, they displayed an indifferent attitude to both, suggesting a low addictive potential.
Any analgesic drug with low addictive potential would be welcome news to those who are concerned with the widespread abuse of prescription opioids among the medical community, patients and public health authorities
"This promising drug candidate was identified through an intensively cross-disciplinary, cross-continental combination of computer-based drug screening, medicinal chemistry, intuition and extensive pre-clinical testing," said Brian Kobilka, a professor of molecular and cellular physiology, and one of the senior researchers in the study.
Scientists from the Stanford University School of Medicine, the University of North Carolina, the University of California, San Francisco and Friedrich Alexander University in Erlangen, Germany all contributed to the study which was published in the journal Nature.
"Opium and its derivatives are perhaps the oldest drugs in the pharmaceutical formulary," said Aashish Manglik, an author of the study from Stanford. "There's some evidence that their use predates written history." However, despite their long history of use, for all opioids – which, aside from morphine, include legal prescription painkillers such as codeine, oxycodone, hydrocodone, oxycontin as well as illicit drugs like heroin – the health risks related to the suppression of the respiratory system remain.
The new compound in question was identified using structures in the body called μ-opioid receptors – which can be found throughout the brain and spinal cord and are part of a wider family of opioid receptors that enable morphine-like drugs to exert their painkilling effects. When morphine or any of its natural or synthetic analogues interacts, or binds, with these receptors, a signalling process is initiated which alters the activities of other proteins inside the cells in which they sit.
Previous research has shown that the painkilling effects of morphine-like drugs are brought about by the drug binding to μ-opioid receptors, causing a cascade of chemical reactions – otherwise known as a molecular pathway, a kind of biological signalling between cells – while their respiration-suppressing effects are caused by a different molecular pathway, induced by the same binding event.
Therefore, to reproduce the beneficial effects of morphine without the negative side effects, you would need to activate the μ-opioid receptors, while only stimulating the molecular pathway responsible for inducing analgesic effects, and not the molecular pathway responsible for respiratory suppression.
"The field had wondered whether a small molecule with just the right chemical features to trip off one pathway, but not the other, could be designed," said Manglik.
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. The researchers then narrowed down the options to a few dozen compounds which looked like the most promising and warranted further examination.
Eventually, one compound was identified which strongly activated the "good" molecular pathway without significantly stimulating the "bad" pathway. However, it was not powerful enough to exert the sufficient therapeutic effects, forcing the team to create numerous different versions of the compound until one was observed binding to the μ-opioid receptor better than the original. This workaround led to the final compound – known as PZM21.
Further tests showed that not only did PZM21 not significantly activate the "bad" molecular pathways, it actually prevented stimulation of another kind of receptor – the kappa receptor, which morphine stimulates mildly - and is associated with negative side effects such as uneasiness and, sometimes, hallucinations.
The next step for the researchers will be to conduct further tests, which, if successful, could eventually lead to the first human trials for the drug.