Novel Biased Potent Opioid-Like Agonists as Improved Medications to Treat Chronic and Acute Pain

There are no analgesics to ameliorate chronic pain without adverse side-effects (e.g., respiratory depression, gastrointestinal effects, tolerance, dependence), thus forcing patients into a difficult choice of negative impacts on quality of life. Most of the analgesics used for chronic and acute pain are drugs such as oxycodone, morphine, oxymorphone, and codeine. All of these opioids have been subject to misuse; prescription drug abuse is a severe problem worldwide, causing high mortality and greatly increased emergency room visits.

Recently, research indicated that the analgesic and side-effects of opioids may be separable. Initial work in 1999 by Bohn et al. using -arrestin 2 knockout mice showed that antinociception was enhanced when morphine could not recruit -arrestin. During the next 19 years, Bohn and others showed that the unwanted side-effects of morphine, and presumably all of the classical opioids, such as respiratory depression, life-threatening gastrointestinal effects, tolerance, and dependence, were at least in part due to their ability to recruit -arrestin. Recently, bias factor and a defined therapeutic window were correlated to predict safer analgesics for respiratory depression. Based on this theory,  the compounds that are noted in the preliminary patent of the Drug Design and Synthesis Section (DDSS), Molecular Targets and Medications Discovery Branch (MTMDB), National Institutes on Drug Abuse (NIDA), would be enormously useful. According to in vitro assays, two of these compounds have been shown to be G-protein biased, have potent agonist activity, and do not recruit -arrestin.  Given these characteristics, the compounds should be capable of ameliorating chronic and acute pain without, or with lessened, side-effects. Undoubtedly, there will be a worldwide market for analgesics of this new type. 

The DDSS at NIDA would like to collaborate with companies that have the ability to expedite clinical trials and the introduction of these drugs worldwide. 

Competitive Advantages:

• Potential reduction in risk of respiratory depression
• lessening chronic and acute pain without causing tolerance that would necessitate ever-increasing dosages, or life-threatening side-effects 
• impact prescription drug abuse because of their decreased ability to induce drug dependence

Commercial Applications:

• Acute and chronic pain