AI Article Synopsis
- Morphine, derived from the opium poppy, is commonly used for pain relief but has dangerous side effects like respiratory depression due to its interaction with μ-opioid receptors (μOR).
- Researchers computationally screened over 3 million molecules to find new drug candidates and developed PZM21, which selectively activates μOR while minimizing the recruitment of β-arrestin-2, the pathway linked to harmful effects.
- Unlike morphine, PZM21 is more effective for emotional pain relief, lacks serious side effects like respiratory issues, and does not produce the reinforcing behaviors associated with traditional opioids, making it a promising alternative for pain management.
Article Abstract
Morphine is an alkaloid from the opium poppy used to treat pain. The potentially lethal side effects of morphine and related opioids-which include fatal respiratory depression-are thought to be mediated by μ-opioid-receptor (μOR) signalling through the β-arrestin pathway or by actions at other receptors. Conversely, G-protein μOR signalling is thought to confer analgesia. Here we computationally dock over 3 million molecules against the μOR structure and identify new scaffolds unrelated to known opioids. Structure-based optimization yields PZM21-a potent G activator with exceptional selectivity for μOR and minimal β-arrestin-2 recruitment. Unlike morphine, PZM21 is more efficacious for the affective component of analgesia versus the reflexive component and is devoid of both respiratory depression and morphine-like reinforcing activity in mice at equi-analgesic doses. PZM21 thus serves as both a probe to disentangle μOR signalling and a therapeutic lead that is devoid of many of the side effects of current opioids.
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Source |
|---|---|
| http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5161585 | PMC |
| http://dx.doi.org/10.1038/nature19112 | DOI Listing |
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