In vitro activity of LY393558, an inhibitor of the 5-hydroxytryptamine transporter with 5-HT(1B/1D/2) receptor antagonist properties.
1-[2-[4-(6-fluoro-1H-indol-3-yl)-3,6-dihydro-1(2H)-pyridinyl]ethyl]-3-isopropyl-6-(methylsulphonyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine-2,2-dioxide (LY393558) is a potent inhibitor of [3H]5-hydroxytryptamine ([3H]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 GTPgamma[35S] to human 5-HT(1B) (pK(b)=9.05+/-0.14) and 5-HT(1D) (pK(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 (pK(b)=8.4+/-0.2). In addition, it is an antagonist at the 5-HT(2A) (pK(i)=7.29+/-0.19) and 5-HT(2B) (pK(i)=7.35+/-0.11) receptors. Presynaptic autoreceptor antagonist activity was demonstrated by its ability to potentiate the K(+)-induced outflow of [3H]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.