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“Designer compound” packs morphine’s painkilling punch, without its risk

Aashish ManglikScientists at four institutions including Stanford have designed a compound that appears to pack all the painkilling power of morphine but lacks that drug’s most lethal property: respiratory suppression, which results in some 30,000 drug overdose deaths annually in the United States.

While it's still too early to say for certain, early studies in mice hint that the compound may also be non-addictive. That would come as great news to physicians, patients and public-health authorities deeply concerned about a growing epidemic of addictive-painkiller abuse.

The work -- carried out by Stanford molecular and cellular physiologist Brian Kobilka, MD, instructor Aashish Manglik, MD, PhD, and other researchers at Stanford and three other universities -- is described today in a study in Nature.

Opium and its derivatives are perhaps the oldest drugs in the pharmaceutical formulary. Their use may even predate written history. But respiratory suppression -- the user just stops breathing -- remains a general drawback of opioids, which besides morphine include prescription painkillers codeine, oxycodone, oxycontin, hydrocodone and fentanyl as well as the illicit drug heroin.

Designing a safer molecule hinged on understanding the elaborate three-dimensional structure of the so-called mu opioid receptor, determined by the Kobilka lab in 2012 (the year Kobilka received the Nobel Prize in Chemistry for his receptor-structure work). This in turn enabled detailed analysis of the receptor’s binding pocket, into which opioids fit like a hand in a glove.

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.

Safely reproducing morphine’s benefits meant finding a way to separate those two effects, which was nontrivial but which the collaborators appear to have fully achieved. In mouse experiments, the compound -- called PZM21 -- was as powerful as morphine. In stark contrast with  morphine, though, it had no discernable effect on the mice's breathing.

There's more, as I wrote in our news release about the study:

The new compound’s potential is enhanced by promising early signs, in mouse studies, that it may be less addictive than morphine and related drugs. While this reduced addiction potential remains to be demonstrated definitively in other animal studies, it’s strongly suggested by, among other things, the experimental mice’s indifferent attitude toward solutions containing the compound compared with otherwise identical solutions lacking it.

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. If one of the chambers had been paired with morphine, you'd better believe those mice would have spent substantially more time in the morphine-paired chamber.

Some 2 million Americans age 12 or older have substance-abuse disorders involving prescription pain relievers, with another 600,000 addicted to heroin -- and that four in five new heroin users started out misusing prescription painkillers. We could sure use some relief from that.

Previously: New money for opioid epidemic welcomed to help uninsured, says Stanford's Keith Humpreys, The problem of prescription opioids: "An extraordinarily timely topic"  and Why Stanford Nobel Prize winner Brian Kobilka is a "tour de force of science"
Photo of Aashish Manglik by Norbert von der Groeben

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