Elek Milica, Djokovic Nemanja, Frank Annika, Oljacic Slavica, Zivkovic Aleksandra, Nikolic Katarina, Stark Holger
Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Universitaetsstr. 1, Duesseldorf, NRW, Germany.
Department of Pharmaceutical Chemistry, Faculty of Pharmacy, University of Belgrade, Belgrade, Serbia.
Arch Pharm (Weinheim). 2021 Jun;354(6):e2000486. doi: 10.1002/ardp.202000486. Epub 2021 Feb 22.
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 (D R) and D (D R) receptor subtypes, which belong to the D -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 R and D 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 ) moiety and D R and D R. A radioligand displacement assay determined that all of the ligands showed moderate-to-low nanomolar affinities at D R and D R, with a slight preference for D 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 R affinity and selectivity (pK values of 7.14 [D R] and 8.42 [D R]).
多巴胺是人类大脑中一种重要的神经递质，其浓度改变会导致各种神经系统疾病。我们研究了新型化合物与多巴胺D（D R）和D（D R）受体亚型的结合情况，这些受体亚型属于D -样受体家族。我们进行了10种多巴胺受体配体的合成、计算机模拟和体外表征。将新型配体对接至D R和D R晶体结构中，以研究精确的结合模式。进行了量子力学/分子力学研究，以深入了解新引入的五氟硫烷基（SF ）部分与D R和D R之间分子间相互作用的本质。放射性配体置换试验确定，所有配体在D R和D R上均表现出中等到低纳摩尔的亲和力，对D R略有偏好，这在计算机模拟研究中得到了证实。N-{4-[4-(2-甲氧基苯基)哌嗪-1-基]丁基}-4-(五氟-λ6-硫烷基)苯甲酰胺（7i）表现出最高的D R亲和力和选择性（D R的pK值为7.14，D R的pK值为8.42）。
