New computerised drug development tools have raised hopes of identifying an ideal opioid that will provide potent central analgesia without harmful respiratory effects, be effective when used as chronic treatment, and not be addictive.
A study published online in Nature matched 3 million different compounds to the mu opioid receptor, checked more than 1 million configurations of each, examined 2,500 promising matches by eye, and finally narrowed the field to 23 compounds for experimental testing in in mice.
One of these billions of prospects stood out and led to the development of a drug called PZM21.
The drug provided comparable pain relief to morphine but the effect lasted longer. It reduced pain responses mediated in the central nervous system – the affective component – but not those mediated within the spine.
A commentary by Montreal molecular neurobiologist Professor Brigitte Kieffer said this selective activity had not previously been reported for a mu receptor agonist, and provided hope for new therapeutic options.
“The compound induced less constipation than morphine and did not modify respiratory activity,” she said.
“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.”
She explained that activation of the mu opioid receptor normally triggered two signalling pathways involving either Gi/o or beta-arrestin proteins. There was a strong biological rationale to explain why compounds like PZM21 which did not activate the beta-arrestin pathway could provide better pain relief and fewer adverse side effects.
“Opium has been used medicinally and recreationally for more than 4,000 years because of its remarkable pain-relieving and euphoria-inducing properties,” Professor Kieffer said.
“Today, abuse of prescription opioids – morphine and its derivatives – has escalated, and heroin addiction represents a worldwide health and societal burden.”
In the 1990s it became clear that mu opioid agonists like morphine not only provided pain relief but also induced reward pathways and dependence.
“The realisation that distinct drugs acting at a given receptor can trigger diverse signalling responses has since opened up the possibility of designing ‘biased’ opioids that activate signalling pathways relevant to therapy, but not those that produce unwanted effects,” she said.