Abstract
A series of (arylpiperazinylbutyl)oxindoles as highly potent 5-HT(7) receptor antagonists has been studied for their selectivity toward the 5-HT(1A) receptor and α(1)-adrenoceptor. Several derivatives exhibited high 5-HT(7)/5-HT(1A) selectivity, and the key structural factors for reducing undesired α(1)-adrenergic receptor binding have also been identified. Rapid metabolism, a common problem within this family of compounds, could be circumvented with appropriate substitution patterns on the oxindole carbocycle. Contrary to expectations, none of the compounds produced an antidepressant-like action in the forced swimming test in mice despite sufficiently high brain concentrations. On the other hand, certain analogues showed significant anxiolytic activity in two different animal models: the Vogel conflict drinking test in rats and the light-dark test in mice.
MeSH terms
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Animals
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Anti-Anxiety Agents / chemical synthesis*
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Anti-Anxiety Agents / chemistry
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Anti-Anxiety Agents / pharmacology
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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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Binding Sites
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Brain / metabolism
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CHO Cells
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Cricetinae
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Cricetulus
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Ligands
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Male
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Mice
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Microsomes, Liver / metabolism
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Radioligand Assay
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Rats
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Receptor, Serotonin, 5-HT1A / metabolism
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Receptors, Adrenergic, alpha-1 / metabolism
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Receptors, Serotonin / metabolism*
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / chemistry
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Serotonin Antagonists / pharmacology
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Structure-Activity Relationship
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Tissue Distribution
Substances
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Anti-Anxiety Agents
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Antidepressive Agents
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Indoles
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Ligands
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Piperazines
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Receptors, Adrenergic, alpha-1
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Receptors, Serotonin
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Serotonin Antagonists
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serotonin 7 receptor
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Receptor, Serotonin, 5-HT1A