Premium
Synthesis, in silico, and in vitro studies of novel dopamine D 2 and D 3 receptor ligands
Author(s) -
Elek Milica,
Djokovic Nemanja,
Frank Annika,
Oljacic Slavica,
Zivkovic Aleksandra,
Nikolic Katarina,
Stark Holger
Publication year - 2021
Publication title -
archiv der pharmazie
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.468
H-Index - 61
eISSN - 1521-4184
pISSN - 0365-6233
DOI - 10.1002/ardp.202000486
Subject(s) - chemistry , dopamine receptor d3 , radioligand , dopamine receptor d2 , in silico , stereochemistry , dopamine , affinities , moiety , agonist , receptor , in vitro , biochemistry , biology , neuroscience , gene
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]).