Synthesis, in silico, and in vitro studies of novel dopamine D 2 and D 3 receptor ligands

Dopamine is an important neurotransmitter in the human brain and its altered concentrations can lead to various neurological diseases. We studied the binding of novel compounds at the dopamine D 2 (D 2 R) and D 3 (D 3 R) receptor subtypes, which belong to the D 2 ‐like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D 2 R and D 3 R crystal structures to examine the precise binding mode. A quantum mechanics/molecular mechanics study was performed to gain insights into the nature of the intermolecular interactions between the newly introduced pentafluorosulfanyl (SF 5 ) moiety and D 2 R and D 3 R. A radioligand displacement assay determined that all of the ligands showed moderate‐to‐low nanomolar affinities at D 2 R and D 3 R, with a slight preference for D 3 R, which was confirmed in the in silico studies. N ‐{4‐[4‐(2‐Methoxyphenyl)piperazin‐1‐yl]butyl}‐4‐(pentafluoro‐λ6‐sulfanyl)benzamide ( 7i ) showed the highest D 3 R affinity and selectivity (p K i values of 7.14 [D 2 R] and 8.42 [D 3 R]).