(R)-THIONISOXETINE, A POTENT AND SELECTIVE INHIBITOR OF CENTRAL AND PERIPHERAL NOREPINEPHRINE UPTAKE

Inhibitors of neuronal norepinephrine (NE) uptake are useful for the treatment of a variety of diseases including depression and urinary incontinence. In the present study, we synthesized and evaluated a novel analog of the potent and selective NE uptake inhibitor, nisoxetine. Thionisoxetine more potently inhibited the uptake of [H-3]-NE into hypothalamic synaptosomes and [H-3]-nisoxetine binding to the NE transporter than (R)-nisoxetine. The (R) enantiomer of this compound was significantly more potent than the (S) enantiomer, having a K-i of 0.20 nM in [H-3]-nisoxetine binding. The (R) enantiomer was approximately 70-fold more potent in inhibiting [H-3]-NE uptake when compared to [H-3]-5HT uptake. In rats, (R)-thionisoxetine prevented hypothalamic NE depletion by 6-hydroxydopamine with an ED(50) of 0.21 mg/kg. Depletion of NE in peripheral nerves was accomplished by the administration of metaraminol to rats. In this paradigm, (R)-thionisoxetine prevented the depletion of heart NE with an ED(50) of 3.4 mg/kg and urethral NE with an ED(50) of 1.2 mg/kg. Thus, (R)-thionisoxetine is a potent and selective inhibitor of NE uptake in both central and peripheral tissues.