Aromatic linker variations in novel dopamine D2 and D3 receptor ligands

Abstract 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‐ylethylphenyl) acetamide (6c) demonstrates the highest D 3 R and D 2 R affinity values (p K 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.