title: Novel halogenated analogs of tomoxetine that are potent and selective inhibitors of norepinephrine uptake in brain.
abstract: Halogenated analogs of the potent norepinephrine (NE) uptake inhibitor, tomoxetine, were synthesized and their affinities for the serotonin (5HT) and NE uptake sites evaluated. One of the most potent was the 2-iodo substituted analog (289306) that inhibited [3H]tomoxetine binding to rat cerebral cortex with a Ki of 0.37 nM. The compound also inhibited the uptake of [3H]NE into rat hypothalamic synaptosomes with a Ki of 3.5 nM. This analog was significantly less potent at the 5HT uptake site, as exhibited by a Ki of 25 nM in the inhibition of [3H]paroxetine binding and a Ki of 121 nM in [3H]5HT uptake. The resolved (R) enantiomer (303926) was 10 times more potent as a [3H]NE uptake inhibitor and 29 times more potent as an inhibitor of [3H]tomoxetine binding than the (S) enantiomer (303884). Administration of 289306 to rats prior to an i.c.v. injection of 6-hydroxydopamine prevented the depletion of hypothalamic NE and Epi with ED50 values of 0.28 and 0.47 mg/kg, respectively. Thus, 289306 was a potent inhibitor of NE uptake in vitro and in vivo. In addition, these compounds provide structures for potential ligands for the study of NE uptake sites by autoradiography, PET or SPECT imaging.
authors.affiliation: Central Nervous System Research, Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors.forename: D R
authors.initials: DR
authors.lastname: Gehlert
authors.forename: D A
authors.initials: DA
authors.lastname: Schober
authors.forename: S K
authors.initials: SK
authors.lastname: Hemrick-Luecke
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: R W
authors.initials: RW
authors.lastname: Fuller
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D001921:Brain / Q000378:metabolism*; D007031:Hypothalamus / Q000187:drug effects / Q000378:metabolism; D008297:Male; D009638:Norepinephrine / Q000378:metabolism*; D016627:Oxidopamine / Q000494:pharmacology; D017374:Paroxetine / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000069445:Atomoxetine Hydrochloride; D009638:Norepinephrine; D016627:Oxidopamine; D017374:Paroxetine; D011437:Propylamines; D017367:Selective Serotonin Reuptake Inhibitors