Aromatic linker variations in novel dopamine D₂ and D₃ receptor ligands

Dopamine D₂-like receptors, especially D₂ and D₃ receptor subtypes, are important targets of antipsychotic agents. Many of these antipsychotics share an aliphatic linker element between a protonable amine group and an acyl-like moiety. Here, we have modified this aliphatic linker into phenylmethyl and phenylethyl linkers substituted in different positions. The design, synthesis, and in vitro evaluation of 18 dopamine D₂ and D₃ receptor ligands were performed in this study. Using a radioligand displacement assay, all ligands were found to have modest nanomolar affinity to D₂R and D₃R. N-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}phenyl)acetamide (6c) demonstrates the highest D₃R and D₂R affinity values (pK_i values of 7.83 [D₂R] and 8.04 [D₃R]), featuring a slight preference to D₃R. This derivative can be taken as a reference structure for the development of a new class of D₂R and D₃R ligands.