SKF83959 is a novel triple reuptake inhibitor that elicits anti-depressant activity
Abstract
Aim: SKF83959 (3-methyl-6-chloro-7,8-hydroxy-1-(3-methylphenyl)-2,3,4,5-tetrahydro-1H-3-benzazepine) is an atypical dopamine receptor-1 (D1 receptor) agonist, which exhibits many D1 receptor-independent effects. In the present work, we examined the effects of SKF83959 on monoaminergic transporters in vitro and its anti-depressant activity in vivo.
Methods: Human serotonin transporter (SERT), norepinephrine transporters (NET) or dopamine transporters (DAT) were stably expressed in CHO cells. The uptake kinetics of SERT, NET, and DAT were examined using [3H]-serotonin, [3H]-norepinephrine or [3H]-dopamine, respectively. A triple reuptake inhibitor DOV21947 was used as the positive control. Tail suspension test and forced swimming test were conducted in mice. SKF83959 or DOV21947 (2–8 mg/kg) were intraperitoneally injected 30 min before the tests.
Results: SKF83959 was a competitive inhibitor of SERT (Ki=1.43±0.45 μmol/L), but a noncompetitive inhibitor of NET (Ki=0.60±0.07 μmol/L) and DAT (Ki=9.01±0.80 μmol/L). In contrast, DOV21947 was a competitive inhibitor of SERT (Ki=0.89±0.24 μmol/L) and DAT (Ki=1.47±0.31 μmol/L) and a noncompetitive inhibitor of NET (Ki=0.18±0.04 μmol/L). In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner.
Conclusion: SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.
Keywords:
Methods: Human serotonin transporter (SERT), norepinephrine transporters (NET) or dopamine transporters (DAT) were stably expressed in CHO cells. The uptake kinetics of SERT, NET, and DAT were examined using [3H]-serotonin, [3H]-norepinephrine or [3H]-dopamine, respectively. A triple reuptake inhibitor DOV21947 was used as the positive control. Tail suspension test and forced swimming test were conducted in mice. SKF83959 or DOV21947 (2–8 mg/kg) were intraperitoneally injected 30 min before the tests.
Results: SKF83959 was a competitive inhibitor of SERT (Ki=1.43±0.45 μmol/L), but a noncompetitive inhibitor of NET (Ki=0.60±0.07 μmol/L) and DAT (Ki=9.01±0.80 μmol/L). In contrast, DOV21947 was a competitive inhibitor of SERT (Ki=0.89±0.24 μmol/L) and DAT (Ki=1.47±0.31 μmol/L) and a noncompetitive inhibitor of NET (Ki=0.18±0.04 μmol/L). In mice, both SKF83959 and DOV21947 elicited anti-depressant activity in a dose-dependent manner.
Conclusion: SKF83959 functions as a novel triple reuptake inhibitor in vitro and exerts anti-depressant effects in vivo.