( R)-thionisoxetine, a potent and selective inhibitor of central and peripheral norepinephrine uptake

Abstract

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 [ 3H]-NE into hypothalamic synaptosomes and [ 3H]-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 Ki of 0.20 nM in [ 3H]nisoxetine binding. The ( R) enantiomer was approximately 70-fold more potent ininhibiting [ 3H]-NE uptake when compared to [ 3H]-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.