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Sep 01, 2016
 |  BC Innovations  |  Targets & Mechanisms

Biased against pain

How Epiodyne aims to make opioids safer

In a departure from the rote tweaking of morphinan structures to find better and safer opioids, an academic collaboration has used a powerful, computer-based screen of more than 3 million molecules to identify a new structure that acts as a biased agonist at mu receptors, teasing apart analgesia from abuse liability and respiratory depression. The team, headed by researchers at four universities, is spinning out Epiodyne Inc. to bring the compound to the clinic.

In the study, published Aug. 17 in Nature, researchers from the University of California San Francisco (UCSF), University of North Carolina at Chapel Hill, Stanford University and the University of Erlangen-Nuremberg identified PZM21, a molecule they describe as both a research probe and a therapeutic lead, and demonstrated it has orders of magnitude greater potency at signaling via the receptor's G protein, GNAI1, than its β-arrestin, ARRB2.

"The idea was that if we came up with something that was completely novel in terms of structure, it would likely have novel biology. And as luck would have it, it does," said Bryan Roth, a corresponding author on the paper, professor in the Department of Pharmacology at UNC's Eshelman School of Pharmacy and director of the NIMH Psychoactive Drug Screening Program at NIH's National Institute of Mental Health (NIMH).

Epiodyne has received seed funding from Kleiner Perkins Caufield & Byers and Mission Bay Capital, but is not disclosing the amount of funding or its immediate plans for PZM21. According to Roth, the field has converged on the notion in the last 15 years that GNAI1 signaling mediates pain relief while ARRB2 is responsible for many, if not all, of the side effects of mu receptor activation.

However, a study published two weeks ago in Nature Communications demonstrated the first positive role for ARRB2 in pain management, showing the molecule might help prevent acute pain from becoming chronic (see Box: Bad guy's good side).

While many attempts have been made to design an agonist that can bind the mu receptor and trigger a shift toward a conformation capable of activating GNAI1 but not ARRB2, Roth said that has been "a real challenge."

Trevena Inc., whose platform technology is based on separating signaling via G proteins from signaling via arrestins, has the biased agonists oliceridine and TRV734 in Phase III and Phase I, respectively, for pain. Neither molecule is structurally related to morphine or to PZM21 (see Figure: Breaking form).

Trevena CSO Michael Lark told BioCentury that while both its compounds and PZM21 have better side effect profiles than standard opioids, the fact they have "completely different" chemical structures and distinct pharmacological properties raises the possibility of designing a variety of biased agonists tuned for different clinical applications. "This shows that there is still wiggle room in how we can activate these receptors."

MOR on the brain

In in vitro assays PZM21 bound the mu receptor with a Ki of 1.1 nM and activated GNAI1 signaling with an EC50 of 4.6 nM.

In a standard assay of ARRB2 activation, the compound yielded no detectable signal, although a more sensitive assay revealed a small amount of residual ARRB2 activity, indistinguishable from Trevena's Phase III compound oliceridine (see Distillery, page 22).

PZM21 was also highly selective for the mu receptor over other opioid receptors. It had 500-fold lower affinity at the opioid receptor delta 1, and while it bound the kappa opioid receptor with a Ki of 18 nM, it acted as an antagonist rather...

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