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NIDA. (2016, September 21). Virtual Drug Design Yields Opioid Breakthrough. Retrieved from

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Science Highlight

September 21, 2016
scientist hand with test tubesPhoto by ©iStock/JK1991

Existing opioid medications have a range of side effects that make them problematic as pain treatments, as has been seen in America’s current opioid crisis and overdose epidemic. Morphine and related opioids cause euphoria, making them highly liable to misuse, and they suppress breathing, making fatal overdose a danger; they also produce other effects in the body like constipation. Thus, a top priority for researchers is developing new compounds that can target pain more precisely, without these side effects.

Using new virtual drug screening technology, teams of researchers at Stanford, the University of North Carolina, and the University of California San Francisco synthesized a compound unrelated to known opioids that relieved pain in mice for nearly three hours—much longer than the relief produced by morphine—and with minimal side effects, including reward. The compound, PZM21, selectively relieves central nervous system-mediated pain by activating the mu-opioid receptor via a G-protein coupled receptor pathway while producing minimal breathing suppression, reward, or constipation, which are mediated by the beta-arrestin pathway or action at other receptors. PZM21 had no effect on pain mediated by the spinal cord. This breakthrough highlights the power of computer-based drug design; the researchers were able to screen three million compounds, each in roughly 1.3 million configurations, to arrive at the desired drug effect profile. The unique chemical activity of PZM21 makes it a valuable tool to study opioid receptor biology, and is an important step toward the development of safer pain medications.