Aromatic ring functionalization of benzolactam derivatives: New potent dopamine D₃ receptor ligands

Since the discovery of the dopamine D₃ receptor, an intensive effort has been directed toward the development of potent and selective ligands in order to elucidate the function and potential therapeutic advantages of targeting D₃ receptors. As a part of our efforts, a novel series of substituted benzolactams derivatives was synthesized mostly through palladium-catalyzed reactions. Their affinities on D₁–D₄ receptors were evaluated and the data led us to highly potent D₃ ligands, some of them highly selective for D₃ receptor, compared to the related dopamine receptor subtypes. Functional D₃ activity assays of the most relevant compounds have been carried out revealing antagonist as well as partial agonist activity.