A recent study published in Nature has shed light on the modulation of conformational dynamics of the µ-opioid receptor (µOR) by ligand efficacy, offering insights that could potentially lead to the development of better therapeutics for pain management.

The µ-opioid receptor is a crucial target for pain management, and a deeper molecular understanding of how drugs interact with the receptor could pave the way for improved therapeutics. The study, conducted by Jiawei Zhao, Matthias Elgeti, Evan S. O’Brien, Cecília P. Sár, Amal EI Daibani, Jie Heng, Xiaoou Sun, Elizabeth White, Tao Che, Wayne L. Hubbell, Brian K. Kobilka, and Chunlai Chen, utilized double electron–electron resonance and single-molecule fluorescence resonance energy transfer to elucidate how ligand-specific conformational changes of µOR translate into a broad range of intrinsic efficacies at the transducer level.

The research identified several conformations of the cytoplasmic face of the receptor that interconvert on different timescales, including a pre-activated conformation capable of G-protein binding, and a fully activated conformation that markedly reduces GDP affinity within the ternary complex. The study also highlighted that the interaction of β-arrestin-1 with the µOR core binding site appears less specific and occurs with much lower affinity than the binding of Gi.

The µOR, a family A G-protein-coupled receptor (GPCR), is a significant drug target for analgesia. However, the activation of the µOR by opioids such as morphine and fentanyl may lead to adverse effects with varying severity, including constipation, tolerance, and respiratory depression. The receptor activates Gi/o family G proteins and recruits β-arrestins-1 and 2. Traditionally, it was believed that the analgesic effects of µOR signaling were mediated by G-protein signaling, while respiratory depression was mediated by β-arrestin recruitment. Consequently, ligands that preferentially activate G protein, known as G-protein-biased agonists, were expected to exhibit reduced side effects.

As a result, a series of G-protein-biased ligands were developed, including TRV130, PZM21, mitragynine pseudoindoxyl (MP), and SR-170184. However, recent studies have shown that overly strong G-protein signaling (super-efficacy) is responsible for respiratory depression and that partial agonists with lower efficacy provide a safer therapeutic profile.