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

ND, no data available.

Ligand	In vitro		In vivo		Reference
	G protein activation	β-Arrestin recruitment	Administration and dose	Outcome
Oliceridine (TRV130)	EC50 = 7.94 nM Efficacy = 84%	EC50 = 5.01 nM Efficacy = 15%	ND		(81)
	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 gastrointestinal dysfunction
	ND	ND	Phase 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
	ND	ND	Phase II trial	•2 and 3 mg mitigated severe acute pain over 48 hours	(103)
			Pilot phase: 144 patients
			After pilot phase: 195 patients
			Intravenous, 0.5, 1, 2, or 3 mg every 3 hours
	ND	ND	Phase III trial	•Superior analgesia	(104)
			375 patients	•Reduced respiratory side effects and increased gastrointestinal tolerability
			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)
Mitragynine pseudoindoxyl	EC50 = 1.7 nM Efficacy = 84%	No recruitment at 10 μM	CD-1 mice	•Analgesia	(105)
			Subcutaneous, 0.76 mg/kg	•Limited respiratory depression and constipation
SHR9352	EC50 = 0.77 nM Efficacy = 96%	EC50 = 2.5 nM Efficacy = 18%	C57BL/6J mice and Wistar rats	•Analgesia	(106)
			Subcutaneous, 0.1 mg or	•No constipation
			Intravenous, 0.3 mg
SR-17018	EC50 = 97 nM Efficacy = 75%	No recruitment at 10 μM	C57BL/6J mice	•Analgesia	(107)
			Intraperitoneal, 6 mg/kg	•No respiratory suppression
Herkinorin	EC50 = 0.5 μM	No recruitment at 10 μM	No blood-brain barrier penetration		(108)
PZM21	EC50 = 4.6 nM Efficacy = 76%	No recruitment at 10 μM	C57BL/6J mice	•Dose dependent response	(97)
			Subcutaneous, 40, 20, and 10 mg/kg	•Long-lasting analgesia
				•Decreased respiratory depression and constipation
Cyclopeptide	EC50 = 5.2 nM Efficacy = 80%	No recruitment at 10 μM	ND		(109)