One of the most widely discussed strategies is the ‘biased agonist’ approach. Laura Bohn, a pharmacologist at the Scripps Research Institute in Jupiter, Florida, came up with this concept in 1999 when looking at analgesic responses to morphine in mice engineered without the intracellular signalling molecule beta (β)-arrestin2.
This protein plays a role in dampening cellular responses, including those involving the intracellular G-proteins recruited when opioid receptors are activated. “[Without β-arrestin2, we] found that the analgesic response was actually enhanced and prolonged and [we] realised that the tolerance went away — you can chronically treat [the mice] with morphine and they remain responsive to it,” says Bohn. She also found the mice did not experience respiratory depression, which led to the idea that minimising the β-arrestin2 response to opioids could provide a safer route to pain relief.
Source: Courtesy of Laura Bohn
Since then, Bohn has been looking for a drug that, when bound, would change the receptor’s shape to bias its response in favour of the pathway that recruits G-proteins and leads to pain relief, as opposed to the β-arrestin2 pathway, which seems to control many of the adverse side effects. Opioids, such as fentanyl, show the opposite bias and are more likely to induce respiratory suppression at lower doses than other drugs.
Bohn has since identified six piperidine-based mu (μ) receptor agonists that provided effective pain relief with fewer respiratory problems. The addictive nature of these compounds is still unclear, but Bohn is hopeful that they will not lead to tolerance. “We are hoping that if we can develop a compound that doesn’t produce tolerance, doses can be kept low and pain can be managed,” she explains.
Nevertheless, whether or not Bohn’s biased agonist approach really can provide the required clinical advances remains to be seen. “It’s a good step forward but I don’t know if it’s going to be the magic pill that everyone is hoping for,” says Gavril Pasternak, clinician and pharmacologist at the Memorial Sloan Kettering Cancer Center in New York.
In fact, Trevena’s new opioid, Olinvo, is based on the biased agonist principle and trial results so far suggest its advantages over existing opioids may be more limited than hoped. Phase III trial results in post-surgical patients released by the company in February 2017 showed only trends to improvement over morphine with respect to side effects.