Abstract
In a wide search program toward new, efficient, and fast-acting antidepressant drugs, we have prepared series of new compounds having an (aryl)(aryloxy)methyl moiety linked directly or through a methylene chain to different substituted and unsubstituted cycles (isoquinoline, piperazine, piperidine, tetrahydropyran, or cyclopentane). These compounds have been evaluated for their affinities for serotonin (5-HT) transporter (SERT) and 5-HT(1A) and 5-HT(2A) receptors. Racemic mixtures of 4-[(aryl)(aryloxy)methyl]piperidine derivatives showed much higher affinity values for SERT than fluoxetine and resulted in lack of affinity for 5-HT(1A) and 5-HT(2A) receptors. Some of these racemic mixtures were resolved to their enantiomers and tested for binding to norepinephrine (NE) transporter (NET), dopamine (DA) transporter (DAT), and alpha(2) receptor. Several of these enantiomers [(-)-15b, (-)-15j, (-)-15t, (+)-15u] displayed a dual binding profile with affinities for SERT and NET with K(i) < 25 nM and a NET/SERT ratio <10. Compound (-)-15j (coded as F-98214-TA for development studies) showed a dual binding profile with very high affinity values for SERT and NET (K(i) = 1.9 and 13.5 nM, respectively), and further pharmacological characterization is in progress for its evaluation as a antidepressant.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adrenergic Uptake Inhibitors / chemical synthesis*
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Adrenergic Uptake Inhibitors / chemistry
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Adrenergic Uptake Inhibitors / pharmacology
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Animals
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Antidepressive Agents / chemical synthesis*
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Antidepressive Agents / chemistry
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Antidepressive Agents / pharmacology
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Brain / metabolism
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Carrier Proteins / metabolism*
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Fluoxetine / analogs & derivatives*
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Fluoxetine / chemistry
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In Vitro Techniques
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Male
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Membrane Glycoproteins / metabolism*
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Membrane Transport Proteins*
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Morpholines / chemistry
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Nerve Tissue Proteins*
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Norepinephrine / metabolism
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Norepinephrine Plasma Membrane Transport Proteins
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Piperidines / chemical synthesis*
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Piperidines / chemistry
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Piperidines / pharmacology
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Radioligand Assay
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Rats
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Rats, Wistar
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Reboxetine
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Receptor, Serotonin, 5-HT1A / metabolism
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Receptor, Serotonin, 5-HT2A / metabolism
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Selective Serotonin Reuptake Inhibitors / chemical synthesis*
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Selective Serotonin Reuptake Inhibitors / chemistry
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Selective Serotonin Reuptake Inhibitors / pharmacology
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Serotonin / metabolism
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Serotonin Plasma Membrane Transport Proteins
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Stereoisomerism
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Structure-Activity Relationship
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Symporters / metabolism*
Substances
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Adrenergic Uptake Inhibitors
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Antidepressive Agents
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Carrier Proteins
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Membrane Glycoproteins
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Membrane Transport Proteins
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Morpholines
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Nerve Tissue Proteins
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Norepinephrine Plasma Membrane Transport Proteins
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Piperidines
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Receptor, Serotonin, 5-HT2A
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Serotonin Plasma Membrane Transport Proteins
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Serotonin Uptake Inhibitors
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Slc6a2 protein, rat
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Slc6a4 protein, rat
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Symporters
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Fluoxetine
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Receptor, Serotonin, 5-HT1A
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nisoxetine
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Serotonin
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Reboxetine
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Norepinephrine