Biased ligands at opioid receptors: Current status and future directions

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Science Signaling  06 Apr 2021:
Vol. 14, Issue 677, eaav0320
DOI: 10.1126/scisignal.aav0320


  • Fig. 1 Signaling and regulatory paradigms of opioid receptors.

    (Left) Agonist stimulation leads to the coupling of opioid receptors to heterotrimeric G proteins, resulting in a reduction in cAMP abundance, a decreased Ca2+ response, and the activation of GIRK channels. (Middle) Subsequently, the receptor is phosphorylated by GRKs, which results in β-arrestin recruitment, receptor desensitization, and internalization. β-Arrestins also mediate the activation of various signaling pathways, including those of the MAPKs, ERK1/2, and p38. (Right) Gαi protein and β-arrestins can also interact with each other and form a complex to mediate downstream signaling, such as ERK activation.

  • Fig. 2 Chemical space shared by the currently reported G protein–biased ligands at μ-OR and κ-OR.

    (A) Chemical structures of currently described G protein–biased ligands at the μ-OR and κ-OR. Of these, nalfurafine shows moderate selectivity at κ-OR compared with μ-OR and δ-OR, whereas the others exhibit substantial selectivity for the different receptors. (B) The different types of ligand bias that can be potentially manifested by opioid receptors. Ligands may elicit differential coupling of heterotrimeric G proteins versus β-arrestins, as well as differential coupling of G protein subtypes and β-arrestin isoforms. In addition, some ligands may also elicit context-specific bias, for example, in different tissues expressing opioid receptors.

  • Fig. 3 Structure-based discovery and optimization of a G protein–biased μ-OR ligand, PZM21.

    Schematic representation of the discovery and optimization pipeline using structure-guided virtual screening. Using the crystal structure of the μ-OR, a large set of chemical compounds was virtually screened, which was followed by the identification of a handful of lead compounds for further testing. Subsequent optimization and structure-function relationship studies yielded PZM21, which is a G protein–biased μ-OR partial agonist, and produced desirable analgesic activity in vivo without the typical side effects observed with other μ-OR agonists, such as morphine.


  • Table 1 G protein–biased ligands at the μ-OR.

    ND, no data available.

    LigandIn vitroIn vivoReference
    G protein activationβ-Arrestin recruitmentAdministration and
    Oliceridine (TRV130)EC50 = 7.94 nM
    Efficacy = 84%
    EC50 = 5.01 nM
    Efficacy = 15%
    EC50 = 8 nM
    Efficacy = 71%
    Efficacy = 14%C57BL/6J mice•Peak analgesia in 5 min(82)
    Subcutaneous, 1 mg/kg•Reduced central
    nervous system
    depression and
    NDNDPhase I trial•Well tolerated(102)
    18 healthy volunteers•Nausea and vomiting
    at 7 mg limited further
    dose escalation
    Intravenous, dose
    range 0.15 to 7 mg
    NDNDPhase II trial•2 and 3 mg mitigated
    severe acute pain over
    48 hours
    Pilot phase:
    144 patients
    After pilot phase:
    195 patients
    Intravenous, 0.5, 1, 2, or
    3 mg every 3 hours
    NDNDPhase III trial•Superior analgesia(104)
    375 patients•Reduced respiratory
    side effects and
    Intravenous: 1.5 mg
    loading dose followed
    by 0.1-mg, 0.35-mg, or
    0.5-mg doses
    Morphine (4-mg
    loading dose; 1-mg
    demand dose)
    EC50 = 1.7 nM
    Efficacy = 84%
    No recruitment at
    10 μM
    CD-1 mice•Analgesia(105)
    0.76 mg/kg
    •Limited respiratory
    depression and
    SHR9352EC50 = 0.77 nM
    Efficacy = 96%
    EC50 = 2.5 nM
    Efficacy = 18%
    C57BL/6J mice and
    Wistar rats
    Subcutaneous, 0.1 mg
    •No constipation
    Intravenous, 0.3 mg
    SR-17018EC50 = 97 nM
    Efficacy = 75%
    No recruitment at
    10 μM
    C57BL/6J mice•Analgesia(107)
    6 mg/kg
    •No respiratory
    HerkinorinEC50 = 0.5 μMNo recruitment at
    10 μM
    No blood-brain barrier
    PZM21EC50 = 4.6 nM
    Efficacy = 76%
    No recruitment at
    10 μM
    C57BL/6J mice•Dose dependent
    Subcutaneous, 40, 20,
    and 10 mg/kg
    •Long-lasting analgesia
    •Decreased respiratory
    depression and
    CyclopeptideEC50 = 5.2 nM
    Efficacy = 80%
    No recruitment at
    10 μM
  • Table 2 G protein–biased ligands at the κ-OR.

    LigandIn vitroIn vivoReference
    G protein
    Administration and doseOutcome
    6′-GNTIEC50 = 1.6 nM
    Efficacy = 64%
    No recruitment
    C57BL/6J mice•Analgesia(110)
    Spinal cord injection, 10 to
    30 nmol
    •No aversion
    RB-64 (22-thiocyanatosalvinorin A)EC50 = 5.22 nM
    Efficacy = 99%
    EC50 = 1130 nM
    Efficacy = 126%
    C57BL/6J mice•Long lasting analgesic(70)
    Subcutaneous, 3 mg/kg•No sedative effect
    Triazole 1.1EC50 = 77 nM
    Efficacy = 101%
    EC50 = 4955 nM
    Efficacy = 98%
    C57BL/6J mice•Analgesia(72)
    Subcutaneous dose•Antipruritic
    Analgesia: 5, 15, and 30 mg/kg•No sedation or dysphoria
    Antipruritic: 1 and
    3 mg/kg
    HS666EC50 = 35.7 nM
    Efficacy = 50%
    EC50 = 449 nM
    Efficacy = 24%
    CD-1 mice•Time and dose dependent(111, 112)
    6.02 nmol
    •Antinociceptive response
    •Respiratory suppression
    NalfurafineEC50 = 1.4 nM
    EC50 = 110 nM
    Rats and primates•Analgesic(113)
    Subcutaneous, 1 mg/kg•Antipruritic
    •No dysphoria or aversion
    EC50 = 0.11 nM
    Efficacy = 111%
    EC50 = 1.4 nM
    Efficacy = 129%
    CD-1 mice•Analgesic(73)
    Subcutaneous, 10 μg/kg•Antipruritic
    •No aversion

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