Abstract
The finding that ergotamine binds serotonin receptors in a less conserved extended binding pocket close to the extracellular entrance, in addition to the orthosteric site, allowed us to obtain 5-HT7R antagonist 6 endowed with high affinity (Ki=0.7 nM) and significant 5-HT1AR selectivity (ratio>1428). Compound 6 exhibits in vivo antidepressant-like effect (1 mg/kg, ip) mediated by the 5-HT7R, which reveals its interest as a putative research tool or pharmaceutical in depression disorders.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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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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Body Temperature / drug effects
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Female
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Hypothermia / chemically induced
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Indoles / chemical synthesis
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Indoles / chemistry*
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Indoles / pharmacology
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Isoquinolines / chemical synthesis
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Isoquinolines / chemistry*
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Isoquinolines / pharmacology
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Male
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Mice, Inbred C57BL
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Molecular Dynamics Simulation
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Motor Activity / drug effects
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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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Stereoisomerism
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Structure-Activity Relationship
Substances
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1-(6-(3,4-dihydroisoquinolin-2(1H)-yl)hex-3-en-1-yl)-1,3-dihydro-2H-indol-2-one
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Antidepressive Agents
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Indoles
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Isoquinolines
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Receptors, Serotonin
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Serotonin Antagonists
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serotonin 7 receptor