Aromatic linker variations in novel dopamine D 2 and D 3 receptor ligands.

Dopamine D 2 -like receptors, especially D 2 and D 3 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 D 2 and D 3 receptor ligands were performed in this study. Using a radioligand displacement assay, all ligands were found to have modest nanomolar affinity to D 2 R and D 3 R. N-(4-{2-[4-(2-Methoxyphenyl)piperazin-1-yl]ethyl}phenyl)acetamide (6c) demonstrates the highest D 3 R and D 2 R affinity values (pK i values of 7.83 [D 2 R] and 8.04 [D 3 R]), featuring a slight preference to D 3 R. This derivative can be taken as a reference structure for the development of a new class of D 2 R and D 3 R ligands.