Strategy for making safer opioids bolstered

Compounds have been made that activate only the G-protein signalling pathway when bound to the µ-opioid receptor — the target of opioid pain relievers. These compounds lack one of the main side effects of currently used opioids.

Effective pain management is one of the greatest challenges of modern medicine. Opioids such as morphine and fentanyl are the preferred clinical treatments for moderate to severe pain because of their strong analgesic (pain-relieving) effects. But the ongoing epidemic of deaths from respiratory depression induced by opioid overdoses highlights the need for safer analgesics. Writing in Cell, Schmid et al.1 report a series of compounds that provides a much-needed proof of principle of a strategy for making safer opioids.

It is estimated that more than 100 million adults suffer from chronic pain in the United States alone, and that this costs up to US$635 billion per year in medical treatment and lost workforce productivity2. The most commonly used drugs for pain management include opioids, non-steroidal anti-inflammatory drugs (NSAIDs) and paracetamol (acetaminophen). However, these treatments can have numerous side effects. For example, NSAIDs can cause cardiovascular complications, gastrointestinal bleeding and renal disease, and acetaminophen is toxic to the liver.

Opioids mainly target the µ-opioid receptor (µOR) in neuronal membranes. Activation of the receptor modulates the behaviour of several membrane ion channels along the nociceptive pathways — those neuronal pathways in the nervous system that respond exclusively to painful or potentially painful stimuli — and in central pain-processing centres. But the side effects associated with these drugs include respiratory depression, constipation and addiction. The development of safe, abuse-free opioid analgesics therefore represents a long-standing scientific challenge3.

Several strategies have been used to try to develop analgesics that activate the µOR but which are free from adverse side effects. These include the development4 of partial activators of the µOR; of compounds that activate the µOR but block other opioid-receptor subtypes5; and of compounds that are restricted to the peripheral, rather than the central, nervous system6. Other approaches have involved molecules that bind to the µOR only in acidic environments7 (which are often associated with damaged tissue), and compounds that target opioid receptors formed from more than one subtype8. A more-recent strategy has been to make allosteric modulators of the µOR — compounds that activate it by binding to a region on the receptor other than its active site9. Each of these approaches has enhanced our understanding of the µOR system, but has not led to the identification of a safe analgesic.

In the past few years, it has become increasingly evident that different ligand molecules can activate receptors in different ways10. In the case of G-protein-coupled receptors (the family of receptors to which the µOR belongs), some ligands selectively activate a signalling pathway that involves the eponymous G protein, whereas others activate signalling through a protein called β-arrestin-2. This selectivity is called biased agonism.

Morphine has no bias for the G-protein or β-arrestin-2 signalling pathways. In 1999, a study11 showed that the analgesic effect of morphine is enhanced in mice that lack β-arrestin-2 compared to the effect in wild-type mice, and that several of the drug’s side effects were reduced. Other studies have since shown similar effects of morphine in mice in which the expression of β-arrestin-2 has been downregulated or inhibited12,13. These findings support the idea14 that opioid agonists with a strong bias towards G-protein-mediated signalling will retain their analgesic properties, but produce fewer side effects than unbiased opioids. Several laboratories have since identified G-protein-biased µOR agonists4,15,16,17,18,19 many of which clearly separate analgesia from adverse side effects. One of these compounds, known as TRV130, is currently in phase III clinical trials16. But how well the G-protein bias of these compounds correlates with analgesic efficacy and the reduction of unwanted side effects is not clear.

Schmid et al. tackle the issue of biased opioid signalling head on, and suggest a way to develop analgesic opioids that do not cause respiratory depression. The authors used a previously unreported, selective µOR agonist as a starting point, and synthesized analogues of the compound that contained modifications in two regions of the molecule. They then assessed the analogues in vitro for signalling bias, and in vivo for analgesic efficacy and effects on respiratory depression in mice. All of the compounds were found to be µOR agonists and produced µOR-dependent analgesia.

The authors observed a robust relationship between in vitro G-protein bias and in vivo analgesia and respiratory depression: compounds that exhibited higher G-protein bias were stronger pain relievers and caused less respiratory depression. For example, they observed that fentanyl and one of their new compounds (SR-11501; Fig. 1a) exhibit arrestin bias and have a narrow, threefold therapeutic window — that is, the dose of the compounds at which analgesia occurs is approximately three times lower than the dose at which respiratory depression occurs. By contrast, another compound (SR-17018; Fig. 1b) has a robust G-protein bias and a more than 25-fold therapeutic window.

Figure 1 | Signalling preferences correlate with the physiological effects of opioids. Schmid et al.1 prepared compounds that bind to and activate the µ-opioid receptor (µOR) — the biological target of opioid painkillers. a, µOR activation by some compounds, such as SR-11501, triggers signalling through two pathways: the G-protein pathway and the β-arrestin-2 pathway. Such compounds are pain relievers in mice, but cause respiratory depression as a side effect. b, By contrast, compounds such as SR-17018, which trigger only G-protein-mediated signalling, retain their pain-relieving activity but do not cause respiratory depression.

Schmid and colleagues report that SR-17018 does not activate the β-arrestin-2 signalling pathway in vitro even at high concentrations, and does not block arrestin recruitment by classic µOR agonists. These results suggest that SR-17018 stabilizes a conformation of µOR that has no affinity for β-arrestin-2, supporting the idea that the pharmacological effects of SR-17018 are attributable solely to its G-protein bias. This distinguishes SR-17018 from previously reported µOR ligands.

These results are exciting, but it remains to be seen whether G-protein-biased compounds could be developed as non-addictive opioid analgesics. A few promising drug candidates have been identified that might help to answer this question — for example, in mice, the preclinical candidates PZM2117 and mitragynine pseudoindoxyl19 exhibit some G-protein bias and clearly separate µOR-mediated analgesia from adverse side effects, including respiratory depression, constipation and capacity for abuse. However, a study in rodents indicates that TRV130 retains the potential for abuse20.

Nevertheless, compounds that have similar properties to those identified by Schmid and colleagues are strong candidates for the development of truly safe analgesics. Rational approaches to the design of such a drug will require the identification of the amino-acid residues in the µOR’s binding pocket that are responsible for biased agonism. A long-term goal must therefore be to generate crystals of the receptor in its G-protein-biased and arrestin-biased conformations, so that the structures can be solved using X-ray crystallography. The compounds identified by Schmid et al. should also inform our understanding of signalling through G-protein-coupled receptors in general. Given that such receptors are implicated in many diseases, this could pave the way for the development of numerous drugs that have minimal side effects.

Nature 553, 286-288 (2018)

doi: 10.1038/d41586-018-00045-1
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Updates & Corrections

  • Correction 31 January 2018: The article incorrectly stated that more than 100,000 adults suffer from chronic pain in the United States. The correct figure is more than 100 million adults.


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