Structural Insights Accelerate the Discovery of Opioid Alternatives

Tao Che, Bryan L. Roth

Research output: Contribution to journalReview articlepeer-review

18 Scopus citations


Opioids such as morphine and oxycodone are analgesics frequently prescribed for the treatment of moderate or severe pain. Unfortunately, these medications are associated with exceptionally high abuse potentials and often cause fatal side effects, mainly through the mu -opioid receptor (MOR). Efforts to discover novel, safer, and more efficacious analgesics targeting MOR have encountered challenges. In this review, we summarize alternative strategies and targets that could be used to develop safer nonopioid analgesics. A molecular understanding of G protein-coupled receptor activation and signaling has illuminated not only the complexities of receptor pharmacology but also the potential for pathway-selective agonists and allosteric modulators as safer medications. The availability of structures of pain-related receptors, in combination with high-throughput computational tools, has accelerated the discovery of multitarget ligands with promising pharmacological profiles. Emerging clinical evidence also supports the notion that drugs targeting peripheral opioid receptors have potential as improved analgesic agents.

Original languageEnglish
Pages (from-to)739-761
Number of pages23
JournalAnnual review of biochemistry
StatePublished - Jun 20 2021


  • Analgesic
  • GPCR
  • Nonopioid
  • Opioid receptor
  • Opioids
  • Side effects


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