LY248686, A New Inhibitor of Serotonin and Norepinephrine Uptake

Abstract

LY248686 is an inhibitor of serotonin (S-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 sacrifi ce, 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 KEY WORDS: Uptake; Inhibitor; Serotonin; Norepineph rineThe extent of inhibition of serotonin (5-hydroxytrypta mine; 5-HT) and norepinephrine (NE) uptake by the tricyclic tertiary amine-containing antidepressant drugs depends on their relative degrees of metabolic N-demethylation. Amitriptyline, an inhibitor of 5-HT and NE uptake in nerve-ending preparations (synap tosomes), is converted in vivo to nortriptyline, a po tent and selective inhibitor of NE uptake, while imipra mine, a selective inhibitor of 5-HT uptake, is converted to desipramine, another potent and selective inhibitor

Comparative Affinity of Duloxetine and Venlafaxine for Serotonin and Norepinephrine Transporters in vitro and in vivo, Human Serotonin Receptor Subtypes, and Other Neuronal Receptors

“…Uptake of monoamines was determined according to method of Wong et al (1993) . Accumulation of radioactivity at 4 Њ C represented non-specific uptake and was subtracted from each sample.…”

“…Accumulation of radioactivity at 4 Њ C represented non-specific uptake and was subtracted from each sample. The uptake of 5-HT into platelets from humans was conducted according to the method of Wong et al (1993).…”

“…Ex vivo uptake was determined in groups of five Sprague-Dawley male rats (Harlan Sprague-Dawley) weighing 100-150 gm according to the method of Wong et al (1993). Briefly, the rats were treated with specified doses of drugs either by the subcutaneous (s.c.) or oral route for one hour and then euthanized by decapitation.…”

“…Studies comparing the efficacy of tricyclic antidepressants with selective 5-HT reuptake inhibitors (SSRI) suggest that tricyclic antidepressants may be slightly more efficacious (Nelson 1998;Anderson 2000) but, arguably, compounds with adequate dual uptake inhibition have not been thoroughly evaluated clinically. In order to test the hypothesis that agents endowed with the ability to block both 5-HT and NE uptake would have supplemental efficacy in the treatment of depression, compounds such as duloxetine (Wong et al 1993;Wong 1998) and venlafaxine (Muth et al 1986; for review see Artigas 1995) with combined 5-HT and NE uptake inhibitor (SNRI) properties in a single molecule have been developed. Duloxetine and venlafaxine have both been shown to be clinically effective antidepressants (Berk et al 1997;Mendels et al 1993;Schweizer et al 1994).…”

“…Duloxetine potently inhibits 5-HT and NE uptake processes in vitro and in vivo at similar doses (Kasamo et al 1996;Béïque et al 1998;Wong et al 1993;Wong 1998). However, venlafaxine has been shown to display relatively low affinity for NE uptake into rat synaptosomes compared to 5-HT uptake and for the human NE transporter versus the 5-HT transporter (Bolden-Watson and Richelson 1993;Béïque et al 1998;Tatsumi et al 1997).…”