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.
Pullar
I A
IA
Eli Lilly and Company, Lilly Research Centre Ltd., Erl Wood Manor, Windlesham, GU20 6PH, Surrey, UK. pullar@lilly.com
Boot
J R
JR
Carney
S L
SL
Cohen
M L
ML
Colvin
E M
EM
Conway
R G
RG
Hardy
C H
CH
Lucaites
V L
VL
Nelson
D L
DL
Schenck
K W
KW
Tomlinson
R
R
Wedley
S
S
D000818:Animals; D001667:Binding, Competitive; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003499:Cyclic S-Oxides / Q000378:metabolism / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D026901:Membrane Transport Proteins; D051379:Mice; D009419:Nerve Tissue Proteins; D009638:Norepinephrine / Q000493:pharmacokinetics; D011188:Potassium / Q000494:pharmacology; D011817:Rabbits; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin / Q000187:drug effects* / Q000378:metabolism; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000378:metabolism / Q000493:pharmacokinetics; D012702:Serotonin Antagonists / Q000378:metabolism / Q000494:pharmacology*; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D013462:Sulfur Radioisotopes; D018170:Sumatriptan / Q000494:pharmacology; D013829:Thiadiazines / Q000378:metabolism / Q000494:pharmacology*; D014316:Tritium; D014661:Vasoconstriction / Q000187:drug effects
D002352:Carrier Proteins; D003499:Cyclic S-Oxides; C470302:HTR1B protein, human; C446282:LY 393558; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D044302:Receptor, Serotonin, 5-HT1B; D044346:Receptor, Serotonin, 5-HT1D; D044402:Receptor, Serotonin, 5-HT2A; D044403:Receptor, Serotonin, 5-HT2B; D044405:Receptor, Serotonin, 5-HT2C; D011985:Receptors, Serotonin; C493230:SLC6A4 protein, human; D012702:Serotonin Antagonists; D050486:Serotonin Plasma Membrane Transport Proteins; D017366:Serotonin Receptor Agonists; C493231:Slc6a4 protein, mouse; D013462:Sulfur Radioisotopes; D013829:Thiadiazines; D014316:Tritium; D012701:Serotonin; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D018170:Sumatriptan; D011188:Potassium; D009638:Norepinephrine