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Safer Pain-Killing Drug Candidate Discovered

Fentanyl patch products

Fentanyl patch products (Alcibiades, Wikimedia Commons)

18 August 2016. A research team from the U.S. and Germany identified a chemical molecule with pain-killing properties of opioids, but apparently without the dangerous side effects. The new drug candidate and the process for its development are described in yesterday’s issue of the journal Nature (paid subscription required).

The researchers from University of California in San Francisco — with colleagues at Stanford University, University of North Carolina in Chapel Hill, and Friedrich-Alexander University Erlangen-Nürnberg in Germany — are seeking new treatments for pain without the adverse effects of today’s opioid-based prescription pain killers. Abuse of opioid pain killers is described by Centers for Disease Control and Prevention as a continuing and growing epidemic. CDC reports that in 2012, physicians in the U.S. wrote 259 million prescriptions for pain killers, enough for one bottle of pills for every adult in the country. As of July 2014, according to the CDC, 46 people die each day in the U.S. from an overdose of prescription pain killers.

The team took the approach of finding a completely new chemistry rather than working with existing drugs. Current opioid drugs target mu-opioid receptors to reduce the intensity of pain signals to the brain, particularly regions of the brain controlling emotion, which reduces effects of the pain stimulus. But these receptors are also found in other parts of the body, with opioid drugs causing release of proteins leading to unwanted side-effects including respiratory problems and gastrointestinal distress.

The lab of biochemistry professor and senior author Brian Shoichet at UC-San Francisco studies protein interactions, particularly molecular binding actions, using mathematical models and algorithms that reveal new drug targets. Co-senior author Brian Kobilka, a Nobel prize-winning biochemist, and colleagues at Stanford are studying the atomic structure of G protein-coupled receptors, found on cell surfaces, including nerve cells, and are targets for as many as half of today’s prescription drugs.

G protein-coupled receptors offer an alternative route to addressing pain signals, and first author Aashish Manglik, a graduate student in Kobilka’s lab, applied algorithms written by Shoichet’s group to simulate actions of G protein-coupled receptors. Manglik looked for signaling pathways that would generate the same pain-killing proteins of mu-opioid receptors, but would work only on nerve cells related to pain. The investigation took a massive effort, testing more than 3 million potential molecules against mu-opioid receptors, covering some 4 trillion separate chemical interactions.

The researchers recruited colleagues in medicinal chemistry and opioids at Friedrich-Alexander University and UNC-Chapel Hill to further evaluate the top molecular candidates from the screening process that only targeted nerve cells causing pain. This investigation yielded the molecule PZM21, a potent G-protein activator that addresses pain like mu-opioid receptors, but without triggering signals to respiratory and other functions. Tests in lab mice confirmed PZM21 relieved pain signals without affecting respiration, while the opioid morphine both relieved pain and caused breathing problems.

The paper identified PZM21 as a promising candidate for a new type of pain-killing drug, but extensive discovery, refinement, and testing lie ahead. Several of the authors, including Kobilka and Shoichet, filed a patent for PZM21. In addition, Shoichet and others founded Epiodyne Inc., a company in San Francisco, incorporated in April 2016 to develop new pain drugs. A regulatory filing in June shows the company already attracted $500,000 in debt and equity seed financing.

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