In vitro activity of LY393558, an inhibitor of the 5-hydroxytryptamine transporter with 5-HT1B/1D/2 receptor antagonist properties

Abstract 1-[2-[4-(6-fluoro-1 H -indol-3-yl)-3,6-dihydro-1(2 H )-pyridinyl]ethyl]-3-isopropyl-6-(methylsulphonyl)-3,4-dihydro-1 H -2,1,3-benzothiadiazine-2,2-dioxide (LY393558) is a potent inhibitor of [ 3 H]5-hydroxytryptamine ([ 3 H]5-HT) uptake into rat cortical synaptosomes (pIC 50 =8.48±0.12). It produces a dextral shift of the 5-HT dose–response curves for the binding of GTPγ[ 35 S] to human 5-HT 1B (p K b =9.05±0.14) and 5-HT 1D (p K b =8.98±0.07) receptors and inhibits the contractile response of the rabbit saphenous vein to the 5-HT 1B/D receptor agonist, sumatriptan (p K b =8.4±0.2). In addition, it is an antagonist at the 5-HT 2A (p K i =7.29±0.19) and 5-HT 2B (p K i =7.35±0.11) receptors. Presynaptic autoreceptor antagonist activity was demonstrated by its ability to potentiate the K + -induced outflow of [ 3 H]5-HT from guinea pig cortical slices (pEC 50 =7.74±0.05 nM) in which the 5-HT transporter had been inhibited by a maximally effective concentration of paroxetine. It is concluded that LY393558 should be an effective antidepressant with the potential to produce an earlier onset of efficacy than selective serotonin uptake inhibitors.