Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats.

Article Details

Citation

Koch S, Hemrick-Luecke SK, Thompson LK, Evans DC, Threlkeld PG, Nelson DL, Perry KW, Bymaster FP

Comparison of effects of dual transporter inhibitors on monoamine transporters and extracellular levels in rats.

Neuropharmacology. 2003 Dec;45(7):935-44.

PubMed ID
14573386 [ View in PubMed
]
Abstract

Compounds that block both serotonin (5-HT) and norepinephrine (NE) transporters have been proposed to have improved antidepressant efficacy. We compared the ability of four dual transporter inhibitors-chlorimipramine, duloxetine, milnacipran and venlafaxine-to block monoamine transporters in vitro and in vivo and increase extracellular monoamines in rat brain. Inhibition of radioligand binding to clonal human monoamine transporters in vitro and in vivo in rats was determined. Extracellular concentrations of 5-HT and NE in rat prefrontal cortex (PFC) were quantified using the microdialysis technique. All compounds blocked binding to human 5-HT and NE transporters, although chlorimipramine and venlafaxine had markedly greater affinity for 5-HT than NE transporters. In vivo, chlorimipramine and duloxetine potently blocked both transporters, milnacipran blocked both with lower potency and venlafaxine only blocked the 5-HT transporter. Chlorimipramine and duloxetine increased robustly and approximately equally monoamine extracellular concentrations. Milnacipran produced only small increases in NE, whereas venlafaxine increased 5-HT markedly at the lower doses and both monoamines at high doses. Thus, the dual transporter inhibitors blocked 5-HT and NE transporters in vitro and in vivo with varying potency. Chlorimipramine, duloxetine, and high dose venlafaxine acted as dual transporter inhibitors in rat PFC and increased extracellular concentrations of the monoamines, indicating functional dual transporter inhibition.

DrugBank Data that Cites this Article

Binding Properties
DrugTargetPropertyMeasurementpHTemperature (°C)
ClomipramineSodium-dependent noradrenaline transporterKi (nM)38N/AN/ADetails
DesipramineSodium-dependent noradrenaline transporterKi (nM)3.8N/AN/ADetails
DesipramineSodium-dependent serotonin transporterKi (nM)179N/AN/ADetails
MilnacipranSodium-dependent noradrenaline transporterKi (nM)200N/AN/ADetails
MilnacipranSodium-dependent serotonin transporterKi (nM)123N/AN/ADetails
VenlafaxineSodium-dependent dopamine transporterKi (nM)7647N/AN/ADetails
VenlafaxineSodium-dependent noradrenaline transporterKi (nM)2483N/AN/ADetails
VenlafaxineSodium-dependent serotonin transporterKi (nM)82N/AN/ADetails