Abstract
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.
MeSH terms
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Animals
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Antidepressive Agents, Second-Generation / metabolism
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Antidepressive Agents, Second-Generation / pharmacology*
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Carrier Proteins / antagonists & inhibitors*
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Carrier Proteins / metabolism
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Cerebral Cortex / drug effects
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Cerebral Cortex / metabolism
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Cyclic S-Oxides / pharmacology
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Guinea Pigs
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Humans
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Male
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Membrane Glycoproteins / antagonists & inhibitors*
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Membrane Glycoproteins / metabolism
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Membrane Transport Proteins*
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Nerve Tissue Proteins*
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Norepinephrine / metabolism
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Piperazines
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Rats
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Receptor, Serotonin, 5-HT2A
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Receptors, Serotonin / drug effects*
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Receptors, Serotonin / metabolism
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Serotonin / metabolism
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Serotonin Antagonists / metabolism
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Serotonin Antagonists / pharmacology*
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Serotonin Plasma Membrane Transport Proteins
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Synaptosomes / drug effects
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Synaptosomes / metabolism
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Thiadiazoles / pharmacology*
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Triazoles / metabolism
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Triazoles / pharmacology*
Substances
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Antidepressive Agents, Second-Generation
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Carrier Proteins
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Cyclic S-Oxides
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LY 367265
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Membrane Glycoproteins
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Membrane Transport Proteins
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Nerve Tissue Proteins
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Piperazines
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Receptor, Serotonin, 5-HT2A
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Receptors, Serotonin
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SLC6A4 protein, human
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Serotonin Antagonists
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Serotonin Plasma Membrane Transport Proteins
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Slc6a4 protein, rat
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Thiadiazoles
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Triazoles
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Serotonin
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nefazodone
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Norepinephrine