Opioid signaling and design of analgesics

Barnali Paul, Sashrik Sribhashyam, Susruta Majumdar

Research output: Chapter in Book/Report/Conference proceedingChapterpeer-review

5 Scopus citations


Clinical treatment of acute to severe pain relies on the use of opioids. While their potency is significant, there are considerable side effects that can negatively affect patients. Their rise in usage has correlated with the current opioid epidemic in the United States, which has led to more than 70,000 deaths per year (Volkow and Blanco, 2021). Opioid-related drug development aims to make target compounds that show strong potency but with diminished side effects. Research into pharmaceuticals that could act as potential alternatives to current pains medications has relied on mechanistic insights of opioid receptors, a class of G-protein coupled receptors (GPCRs), and biased agonism, a common phenomenon among pharmaceutical compounds where downstream effects can be altered at the same receptor via different agonists. Opioids function typically by binding to an active site on the extracellular portion of opioid receptors. Once activated, the opioid receptor initiates a G-protein signaling pathway and/or the β-arrestin2 pathway. The proposed concept for the development of safe analgesics around mu and kappa opioid receptor subtypes has focused on not recruiting β-arrestin2 (biased agonism) and/or having low efficacy at the receptor (partial agonism). By altering chemical motifs on a common scaffold, chemists can take advantage of biased agonism as well as create compounds with low intrinsic efficacy for the desired treatments. This review will focus on ligands with bias profile, signaling aspects of the receptor and probe into the structural basis of receptor that leads to bias and/or partial agonism.

Original languageEnglish
Title of host publicationG Protein-Coupled Receptors - Part B
EditorsArun K. Shukla
PublisherElsevier B.V.
Number of pages24
ISBN (Print)9780323994347
StatePublished - Jan 2023

Publication series

NameProgress in Molecular Biology and Translational Science
ISSN (Print)1877-1173
ISSN (Electronic)1878-0814


  • Analgesia
  • G-protein bias
  • Opioid partial agonists
  • PZM21
  • TM5 ECL2
  • β-Arrestin


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