Dopamine/Serotonin Receptor Ligands. 16. Expanding Dibenz[d,g]azecines to 11- and 12-Membered Homologues. Interaction with Dopamine D₁−D₅ 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.