title: LY248686, a new inhibitor of serotonin and norepinephrine uptake.
abstract: LY248686 is an inhibitor of serotonin (5-hydroxytryptamine; 5-HT) and norepinephrine (NE) uptake in synaptosomal preparations of hypothalamus and cerebral cortex, and 5-HT uptake in human blood platelets, with inhibitor constants near nanomolar concentrations. Upon administration to rats 1 hour before sacrifice, LY248686 caused dose-dependent and parallel decreases of 5-HT and NE uptake in hypothalamus homogenates ex vivo. LY248686 is a positive enantiomer and was slightly more potent than its negative isomer, LY248685, as an inhibitor of 5-HT uptake. Both isomers were only weak inhibitors of dopamine (DA) uptake in striatal synaptosomes. The inhibitory effects on 5-HT and NE uptake after a single administration of LY248686 followed similar time courses and simultaneously persisted for as long as 6 hours. LY248686 in vivo could effectively antagonize the p-chloroamphetamine-induced decreases of 5-HT uptake and levels of 5-HT and 5-hydroxyindoleacetic acid in cerebral cortex, and block the accumulation of 14C-NE in rat hearts. In food deprived rats, LY248686 suppressed food intake synergistically with 5-hydroxytryptophan, a precursor amino acid of 5-HT. Because of its lack of affinity for receptors of 5-HT, NE, DA, acetylcholine, histamine and naloxone, and its ability to inhibit 5-HT and NE uptake simultaneously, LY248686 has a favorable pharmacological profile as a potential antidepressant drug.
authors.affiliation: Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285.
authors.forename: D T
authors.initials: DT
authors.lastname: Wong
authors.forename: F P
authors.initials: FP
authors.lastname: Bymaster
authors.forename: D A
authors.initials: DA
authors.lastname: Mayle
authors.forename: L R
authors.initials: LR
authors.lastname: Reid
authors.forename: J H
authors.initials: JH
authors.lastname: Krushinski
authors.forename: D W
authors.initials: DW
authors.lastname: Robertson
mesh_terms: D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001069:Appetite Regulation / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D000068736:Duloxetine Hydrochloride; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000502:physiology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D013876:Thiophenes / Q000494:pharmacology*
chemical_list: D000928:Antidepressive Agents; D000068736:Duloxetine Hydrochloride; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D017367:Selective Serotonin Reuptake Inhibitors; D013876:Thiophenes