Synthesis of novel lactam derivatives and their evaluation as ligands for the dopamine receptors, leading to a D(4)-selective ligand.

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 D(2)-D(5) receptor subtypes and a functional calcium assay of the target compounds at D(2) and D(5) receptor subtypes were performed. All compounds, except 12a and 12b, showed selectivity towards the D(2)-like receptor subtypes. Selectivity of the indolinone derivatives 11a-d at the D(4) receptors was observed. Compound 11b exhibited a remarkable affinity to hD(4) receptors with K(i) value of 0.04+/-0.02 nm and was >43,000-fold selective over the hD(2) receptor. In the functional assay, all the active compounds were of antagonistic activity.