Abstract
Starting from a benzazepine sulfonamide 5-HT(6) receptor antagonist lead with limited brain penetration, application of a strategy of conformational constraint and reduction of hydrogen bond donor count led to a novel series of tricyclic derivatives with high 5-HT(6) receptor affinity and excellent brain:blood ratios.
MeSH terms
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Animals
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Antidepressive Agents, Tricyclic / chemical synthesis*
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Antidepressive Agents, Tricyclic / pharmacology
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Blood-Brain Barrier / drug effects
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Brain / drug effects*
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Chemistry, Pharmaceutical / methods*
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Cytochrome P-450 CYP3A
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Cytochrome P-450 Enzyme System / chemistry
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Humans
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Hydrogen Bonding
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Microsomes / drug effects
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Models, Chemical
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Molecular Conformation
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Protein Isoforms
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Rats
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Receptors, Serotonin / chemistry*
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Serotonin Antagonists / chemical synthesis*
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Serotonin Antagonists / pharmacology
Substances
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Antidepressive Agents, Tricyclic
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Protein Isoforms
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Receptors, Serotonin
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Serotonin Antagonists
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serotonin 6 receptor
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Cytochrome P-450 Enzyme System
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Cyp3a2 protein, rat
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Cytochrome P-450 CYP3A