title: (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 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.
authors.affiliation: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: S K
authors.initials: SK
authors.lastname: Hemrick-Luecke
authors.forename: D A
authors.initials: DA
authors.lastname: Schober
authors.forename: J
authors.initials: J
authors.lastname: Krushinski
authors.forename: J J
authors.initials: JJ
authors.lastname: Howbert
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: R W
authors.initials: RW
authors.lastname: Fuller
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism*; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism*; D007536:Isomerism; D008297:Male; D008680:Metaraminol / Q000494:pharmacology; D009206:Myocardium / Q000378:metabolism; D009638:Norepinephrine / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D017933:Peripheral Nervous System / Q000187:drug effects / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D027981:Symporters; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism; D014521:Urethra / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493226:Slc6a2 protein, rat; D027981:Symporters; D005473:Fluoxetine; C011386:nisoxetine; C093518:thionisoxetine; D012701:Serotonin; D008680:Metaraminol; D009638:Norepinephrine