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 in inhibiting [3H]-NE uptake when compared to [3H]-5HT uptake. In rats, (R)-thionisoxetine prevented hypothalamic NE depletion by 6-hydroxydopamine with an ED50 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 ED50 of 3.4 mg/kg and urethral NE with an ED50 of 1.2 mg/kg. Thus, (R)-thionisoxetine is a potent and selective inhibitor of NE uptake in both central and peripheral tissues.
journal_name
Life Scijournal_title
Life sciencesauthors
Gehlert DR,Hemrick-Luecke SK,Schober DA,Krushinski J,Howbert JJ,Robertson DW,Wong DT,Fuller RWdoi
10.1016/0024-3205(95)00166-4subject
Has Abstractpub_date
1995-01-01 00:00:00pages
1915-20issue
22eissn
0024-3205issn
1879-0631pii
0024320595001664journal_volume
56pub_type
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