Identification of C10 nitrogen-containing aporphines with dopamine D₁ versus D₅ receptor selectivity

New aporphines containing C10 nitrogen substituents (viz. nitro, aniline or amide moieties), were synthesized and evaluated for affinity at human serotonin 5-HT_1A and 5-HT_2A receptors and at human dopamine D₁, D₂ and D₅ receptors. Two series of analogs were investigated: series A which contain a sole C10 nitrogen substituent on the tetracyclic aporphine core and series B which are 1,2,10-trisubstituted aporphines. Remarkably, compounds from both series lacked affinity for the D₅ receptor, thus attaining D₁ versus D₅ selectivity. Compound 20c was the most potent D₁ ligand identified. Docking studies at D₁ and D₅ receptors indicate that the binding mode of 20c at the D₁ receptor allows for stronger hydrophobic contacts, (primarily with Phe residues) as compared to the D₅ receptor, accounting for its D₁ versus D₅ selectivity. Considering the lack of affinity for the D₅ receptor (and low affinity at other receptors tested), compound 20c represents an interesting starting point for further structural diversification of aporphines as sub-type selective D₁ receptor tools.