The selective norepinephrine reuptake inhibitor, LY368975, reduces food consumption in animal models of feeding.
The compound, LY368975 ((R)-thionisoxetine) is a potent and selective inhibitor of the norepinephrine (NE) reuptake site. We evaluated the in vivo properties of LY368975 in various animal models. In mice, LY368975 prevented heart NE depletion by 6-hydroxydopamine with an ED50 of 1.22 mg/kg. In rats, orally administered LY368975 inhibited 3H-NE uptake into hypothalamic synaptosomes ex vivo with an ED50 of 2.5 mg/kg and 3H-tomoxetine binding to the NE transporter with an ED50 of 2.7 mg/kg. When rats were deprived of food for 18 hr, 10 mg/kg LY368975 was able to suppress food intake 1, 2 and 4 hr after reintroduction of the feed. In nonfasted rats trained to drink sweetened condensed milk, LY368975 produced a dose-dependent reduction in consumption with a 44% decrease at 3 mg/kg. At doses up to 10 mg/kg p.o., LY368975 produced no significant effects on locomotor activity suggesting the compound does not activate or sedate the animals at pharmacologically relevant doses. Therefore, LY368975 is an orally available and centrally active NE reuptake inhibitor that is capable of reducing food consumption in rodents. Compounds of this class may have use in the treatment of obesity and eating disorders.
Gehlert
D R
DR
Neuroscience and Endocrine Research, Lilly Research Laboratories, A Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, USA.
Dreshfield
L
L
Tinsley
F
F
Benvenga
M J
MJ
Gleason
S
S
Fuller
R W
RW
Wong
D T
DT
Hemrick-Luecke
S K
SK
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology*; D000818:Animals; D000069445:Atomoxetine Hydrochloride; D002352:Carrier Proteins / Q000037:antagonists & inhibitors; D004435:Eating / Q000187:drug effects*; D005473:Fluoxetine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000032:analysis / Q000378:metabolism / Q000502:physiology*; D050484:Norepinephrine Plasma Membrane Transport Proteins; D016627:Oxidopamine / Q000494:pharmacology; D017374:Paroxetine / Q000378:metabolism; D011437:Propylamines / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D027981:Symporters
D018759:Adrenergic Uptake Inhibitors; D002352:Carrier Proteins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D011437:Propylamines; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; D027981:Symporters; D005473:Fluoxetine; C093518:thionisoxetine; D017374:Paroxetine; D000069445:Atomoxetine Hydrochloride; D016627:Oxidopamine; D009638:Norepinephrine