LY367265, an inhibitor of the 5-hydroxytryptamine transporter and 5-hydroxytryptamine(2A) receptor antagonist: a comparison with the antidepressant, nefazodone

The potential antidepressant, LY367265 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3, 6-dihydro-1(2H)-pyridinyl]ethyl]-5,6-dihydro-1H,4H-[1,2, 5]thiadiazolo[4.3.2-ij]quinoline-2,2,-dioxide) has been shown to have a higher affinity for the 5-hydroxytryptamine (5-HT) transporter (K(i)=2.3 nM) and 5-HT(2A) (K(i)...

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Bibliographic Details
Published in:European journal of pharmacology 2000-10, Vol.407 (1-2), p.39-46
Main Authors: Pullar, I A, Carney, S L, Colvin, E M, Lucaites, V L, Nelson, D L, Wedley, S
Format: Article
Language:English
Subjects:
Animals
Antidepressive Agents, Second-Generation - metabolism
Antidepressive Agents, Second-Generation - pharmacology
Carrier Proteins - antagonists & inhibitors
Carrier Proteins - metabolism
Cerebral Cortex - drug effects
Cerebral Cortex - metabolism
Cyclic S-Oxides - pharmacology
Guinea Pigs
Humans
Male
Membrane Glycoproteins - antagonists & inhibitors
Membrane Glycoproteins - metabolism
Membrane Transport Proteins
Nerve Tissue Proteins
Norepinephrine - metabolism
Piperazines
Rats
Receptor, Serotonin, 5-HT2A
Receptors, Serotonin - drug effects
Receptors, Serotonin - metabolism
Serotonin - metabolism
Serotonin Antagonists - metabolism
Serotonin Antagonists - pharmacology
Serotonin Plasma Membrane Transport Proteins
Synaptosomes - drug effects
Synaptosomes - metabolism
Thiadiazoles - pharmacology
Triazoles - metabolism
Triazoles - pharmacology
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Summary:The potential antidepressant, LY367265 (1-[2-[4-(6-fluoro-1H-indol-3-yl)-3, 6-dihydro-1(2H)-pyridinyl]ethyl]-5,6-dihydro-1H,4H-[1,2, 5]thiadiazolo[4.3.2-ij]quinoline-2,2,-dioxide) has been shown to have a higher affinity for the 5-hydroxytryptamine (5-HT) transporter (K(i)=2.3 nM) and 5-HT(2A) (K(i)=0.81 nM) receptor than the clinically effective antidepressant, nefazodone. It is a potent inhibitor of [3H]5-HT uptake into rat cortical synaptosomes (IC(50)=3.1 nM) and shows selectivity over that for [3H]noradrenaline (IC(50)>1000 nM). It potentiates potassium-induced [3H]5-HT outflow from prelabelled guinea pig cortical slices both in the presence (EC(50)=950 nM) and absence (EC(50)=250 nM) of a saturating concentration of the 5-HT transport inhibitor, paroxetine, indicating a low level of activity at the 5-HT(1B/1D) autoreceptor. These studies indicate that LY367265 is a putative antidepressant which, because of its 5-HT(2A) receptor antagonist activity, has the potential to produce less sleep disturbance and sexual dysfunction than selective serotonin uptake inhibitors.
ISSN:0014-2999
1879-0712
DOI:10.1016/S0014-2999(00)00728-7