Synthesis, in silico, and in vitro studies of novel dopamine D2 and D3 receptor ligands

Abstract

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 D2 (D2R) and D3 (D3R) receptor subtypes, which belong to the D2-like receptor family. The synthesis, in silico, and in vitro characterization of 10 dopamine receptor ligands were performed. Novel ligands were docked into the D2R and D3R 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 (SF5) moiety and D2R and D3R. A radioligand displacement assay determined that all of the ligands showed moderate-to-low nanomolar affinities at D2R and D3R, with a slight preference for D3R, 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 D3R affinity and selectivity (pKi values of 7.14 [D2R] and 8.42 [D3R]).