Dopamine/serotonin receptor ligands. 16.(1) Expanding dibenz[d,g]azecines to 11- and 12-membered homologues. Interaction with dopamine D(1)-D(5) receptors.
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.
Lehrstuhl für Pharmazeutische/Medizinische Chemie, Institut für Pharmazie, Friedrich-Schiller-Universität Jena, Philosophenweg 14, D-07743 Jena, Germany.
Christoph
C
Enzensperger
Franziska K U
FK
Müller
Bärbel
B
Schmalwasser
Petra
P
Wiecha
Heidi
H
Traber
Jochen
J
Lehmann
D001667:Binding, Competitive; D002460:Cell Line; D065127:Dopamine D2 Receptor Antagonists; D006575:Heterocyclic Compounds, 3-Ring / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D047028:Macrocyclic Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D011869:Radioligand Assay; D011954:Receptors, Dopamine / Q000187:drug effects*; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000037:antagonists & inhibitors; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000819:agonists / Q000037:antagonists & inhibitors; D050638:Receptors, Dopamine D4 / Q000819:agonists / Q000037:antagonists & inhibitors; D050641:Receptors, Dopamine D5 / Q000819:agonists / Q000037:antagonists & inhibitors
D065127:Dopamine D2 Receptor Antagonists; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D047028:Macrocyclic Compounds; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C113776:dopamine D2L receptor; D050638:Receptors, Dopamine D4; D050641:Receptors, Dopamine D5