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

LigandIn vitroIn vivoReference
G protein
activation
β-Arrestin
recruitment
Administration and doseOutcome
6′-GNTIEC50 = 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 1.1EC50 = 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
observed
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)
Intracerebroventricular,
6.02 nmol
•Antinociceptive response
•Respiratory suppression
NalfurafineEC50 = 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