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New Morphine Alternative Kills Pain Without the OD Risk

Early indications are that it's not addictive either, say researchers.

Researchers based at Stanford University have developed a morphine alternative that offers comparable painkilling but largely without the overdose risk. Moreover, early experiments targeting mice indicate that the compound, which is described Wednesday in Nature, may prove to be less addictive than opiate painkillers.

For the most part, opioids all kill via one mechanism: respiratory suppression. The neurons of the brain's respiratory control center happen to be laden with opioid receptors, and when these receptors are occupied by actual opioids, the effect is that the channels used by the cells for signalling start blinking off. The result is reduced neuronal excitability, and, with it, respiratory suppression.

So, the brain's breathing "pacemaker" slows, and, if it slows enough, the body will find itself starved of oxygen. This may lead to death. In the case of morphine, it leads to some 30,000 deaths annually. This side effect places a fundamental limit on how much morphine can be safely administered to a patient, which then becomes a limit on how much pain can even be suppressed using the drug.

The new compound doesn't have this respiratory effect, though it targets the same neural receptor that opioid compounds do. Recent research has demonstrated that the signalling cascades resulting in painkilling on one hand and respiratory suppression on the other are in fact distinct, despite originating with the same receptor (the mu receptor). With this in mind, the task of the Stanford group was to find new compounds capable of targeting this one receptor in such a way as to trigger the beneficial signalling cascade without triggering the other.

Computational methods now allow for the testing of vast numbers of simulated compounds against simulated neurons. In the initial screening round, the researchers vetted 3 million commercially available or easily synthesized compounds, resulting in a pool of 2,500 compounds that might possibly have the desired properties. The next round of vetting trimmed the field to a few dozen compounds. Then, from this group, the Stanford team looked for the compounds most unlike known opioids, resulting in a new list of 23 candidates. One more cull left only seven possibilities, which were then sent off to a pharmacology lab at the University of North Carolina for further analysis.

The UNC lab found just a single compound that seemed to have the desired quality of not triggering respiratory suppression while still having painkilling (analgesic) properties. The effect, however, wasn't large enough to be therapeutic.

So, the researchers tried tweaking the compound, which is known as PZM21. Eventually, they came up with a version much better at binding the mu receptor. The result was about a thousand times more effective than the originally vetted compound. Finally, it was time to try PZM21 out on mice, where the compound behaved as hoped. Not only did it have about the same analgesic efficacy as morphine while being relatively benign in terms of respiration, the mice showed little interest in the compound from a dependency perspective.

"Strikingly, mice did not show a preference for the testing chamber in which they received PZM21 over the one in which they received saline, and the compound did not induce hyperactivity—signs of addiction-like behaviour in mice," notes McGill University researcher Brigitte Kieffer in a separate Nature commentary.

PZM21 sounds like a pretty amazing solution, but there's still a whole lot of ambiguity. The compound may have further in vivo activities so far unobserved, for one. Two, it's metabolic stability is still somewhat unknown, and it's also unknown how and if animals may acquire a tolerance to the drug.

"Are we getting closer to the ideal pain-reliever?," writes Kieffer. "PZM21 is a leading member of a nascent club of pain-effective [mu receptor] agonists that seem to have reduced risk for abuse. These are not exactly opioids, and structure-based discovery approaches should increase their number and enhance the chances of a successful drug reaching the market at last."