Synthesis of novel lactam derivatives and their evaluation as ligands for the dopamine receptors, leading to a D4-selective ligand Original Research Article

The preparation of some lactam (cyclic amide) derivatives bearing various phenylpiperazinylbutyl side chains attached to the amide nitrogen together with their dopamine receptor affinity study is described. The synthesis of the target compounds involved the preparation of the intermediate bromobutyl derivatives of the appropriate lactam followed by N-alkylation of the appropriate phenylpiperazines with these intermediates. Radioligand binding studies at D2–D5 receptor subtypes and a functional calcium assay of the target compounds at D2 and D5 receptor subtypes were performed. All compounds, except 12a and 12b, showed selectivity towards the D2-like receptor subtypes. Selectivity of the indolinone derivatives 11a–d at the D4 receptors was observed. Compound 11b exhibited a remarkable affinity to hD4 receptors with Ki value of 0.04 ± 0.02 nm and was >43,000-fold selective over the hD2 receptor. In the functional assay, all the active compounds were of antagonistic activity.