Table 2. G protein–biased ligands at the ĸ-OR.

Ligand	In vivo		In vitro		Reference
	G protein activation	β-Arrestin recruitment	Administration and dose	Outcome
6’-GNTI	EC50 = 1.6 nM Efficacy = 64%	No recruitment activity	C57BL/6J mice	•Analgesia	(110)
			Spinal cord injection, 10 to 30 nmol	•No aversion
				•Tolerance
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
			•Aversive
Triazole 1.1	EC50 = 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 observed
			Antipruritic: 1 and 3 mg/kg
HS666	EC50 = 35.7 nM Efficacy = 50%	EC50 = 449 nM Efficacy = 24%	CD-1 mice	•Time and dose dependent	(111, 112)
			Intracerebroventricular, 6.02 nmol	•Antinociceptive response
			•Respiratory suppression
Nalfurafine	EC50 = 1.4 nM (pERK1/2)	EC50 = 110 nM (p38)	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