Abstract
Oxygenated 7-methyl-5,6,7,8,9,14-hexahydrodibenz[d,g]azecines are potent dopamine receptor antagonists, preferentially at D1/D5. We synthesized the hydroxylated, methoxylated, and chlorinated 11-membered and 12-membered homologues of these 10-membered heterocycles. Their affinities for the human cloned D1-D5 receptors (radioligand binding) and functionalities (calcium assay) were measured. Enlarging the dibenzazecines to the corresponding dibenzazacycloundecenes and dibenzazacyclododecenes generally maintains the high antagonistic affinity for D1/D5 but also leads to a compound with a clozapine-like binding profile due to additional affinity for D4.
MeSH terms
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Binding, Competitive
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Cell Line
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Dopamine D2 Receptor Antagonists
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Heterocyclic Compounds, 3-Ring / chemical synthesis*
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Heterocyclic Compounds, 3-Ring / chemistry
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Heterocyclic Compounds, 3-Ring / pharmacology
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Humans
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Ligands
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Macrocyclic Compounds / chemical synthesis*
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology
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Quantitative Structure-Activity Relationship
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Radioligand Assay
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Receptors, Dopamine / drug effects*
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Receptors, Dopamine D1 / agonists
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Receptors, Dopamine D1 / antagonists & inhibitors
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Receptors, Dopamine D2 / agonists
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Receptors, Dopamine D3 / agonists
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Receptors, Dopamine D3 / antagonists & inhibitors
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Receptors, Dopamine D4 / agonists
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Receptors, Dopamine D4 / antagonists & inhibitors
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Receptors, Dopamine D5 / agonists
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Receptors, Dopamine D5 / antagonists & inhibitors
Substances
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Dopamine D2 Receptor Antagonists
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Heterocyclic Compounds, 3-Ring
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Ligands
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Macrocyclic Compounds
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Receptors, Dopamine
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Receptors, Dopamine D1
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Receptors, Dopamine D2
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Receptors, Dopamine D3
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dopamine D2L receptor
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Receptors, Dopamine D4
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Receptors, Dopamine D5