LY248686, a new inhibitor of serotonin and norepinephrine uptake

Neuropsychopharmacology. 1993 Jan;8(1):23-33. doi: 10.1038/npp.1993.4.

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.

MeSH terms

  • Animals
  • Antidepressive Agents / pharmacology*
  • Appetite Regulation / drug effects
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Brain / drug effects*
  • Brain / metabolism
  • Chromatography, High Pressure Liquid
  • Duloxetine Hydrochloride
  • Humans
  • In Vitro Techniques
  • Male
  • Neurotransmitter Uptake Inhibitors / pharmacology*
  • Norepinephrine / physiology*
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin Uptake Inhibitors / pharmacology*
  • Thiophenes / pharmacology*

Substances

  • Antidepressive Agents
  • Neurotransmitter Uptake Inhibitors
  • Serotonin Uptake Inhibitors
  • Thiophenes
  • Duloxetine Hydrochloride
  • Norepinephrine