Abstract
A pharmacophore model for triple reuptake inhibitors and the new class of 1-(aryl)-6-[alkoxyalkyl]-3-azabicyclo[3.1.0]hexanes were recently reported. Further investigation in this area led to the identification of a new series of potent and selective triple reuptake inhibitors endowed with good developability characteristics. Excellent bioavailability and brain penetration are associated with this series of 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-azabicyclo[4.1.0]heptanes together with high in vitro potency and selectivity at SERT, NET, and DAT. In vivo microdialysis experiments in different animal models and receptor occupancy studies in rat confirmed that derivative 17 showed an appropriate profile to guarantee further progression of the compound.
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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Azabicyclo Compounds / chemical synthesis
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Azabicyclo Compounds / chemistry
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Azabicyclo Compounds / pharmacology
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Brain / metabolism
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Depressive Disorder / drug therapy*
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Depressive Disorder / metabolism
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Dopamine / metabolism
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Heptanes / chemical synthesis
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Heptanes / chemistry*
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Heptanes / pharmacology*
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Humans
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Magnetic Resonance Spectroscopy
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Male
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Mass Spectrometry
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Mice
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Microdialysis
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Models, Molecular
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Neurotransmitter Uptake Inhibitors / chemical synthesis
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Neurotransmitter Uptake Inhibitors / chemistry*
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Neurotransmitter Uptake Inhibitors / pharmacology*
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Norepinephrine / metabolism
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Rats
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Rats, Sprague-Dawley
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Serotonin / metabolism
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Structure-Activity Relationship
Substances
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Antidepressive Agents
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Azabicyclo Compounds
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Heptanes
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Neurotransmitter Uptake Inhibitors
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Serotonin
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Dopamine
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Norepinephrine