Department of Chemistry and Pharmacy, Medicinal Chemistry , Friedrich-Alexander-Universität Erlangen-Nürnberg , Nikolaus-Fiebiger-Str. 10 , 91058 Erlangen , Germany.
J Med Chem. 2019 Nov 14;62(21):9658-9679. doi: 10.1021/acs.jmedchem.9b01085. Epub 2019 Oct 30.
Many subtype-selective dopamine receptor ligands developed for the D-D family incorporate a 1-arylpiperazine-derived primary recognition motif, which is connected to a lipophilic moiety occupying an extended binding pocket (EBP) of the receptor via an aliphatic linker of variable lengths. The evaluation of a novel group of dopamine receptor ligands now showed that highly subtype-selective ligands [up to (D) = 0.25 nM, D/D = 320, D/D = 710 for APH199 ()] can be obtained by choosing a relatively large and conformationally flexible 1-benzyl-1-phenylsemicarbazide substructure to fill the EBP. The novel chemotype APH199 () was found to act as a full agonist at the D receptor showing significant bias toward G protein activation over β-arrestin recruitment in comparison to quinpirole.
许多为 D-D 家族开发的亚型选择性多巴胺受体配体都包含一个来源于 1-芳基哌嗪的主要识别基序，该基序通过一个可变长度的脂肪族连接子与占据受体扩展结合口袋 (EBP) 的亲脂部分相连。对一组新型多巴胺受体配体的评估表明，通过选择相对较大且构象灵活的 1-苄基-1-苯甲脒亚结构来填充 EBP，可以获得高度亚型选择性的配体 [最高 (D) = 0.25 nM，D/D = 320，D/D = 710 用于 APH199 ()]。与喹吡罗相比，新型化学型 APH199 () 被发现作为 D 受体的完全激动剂，在 G 蛋白激活方面表现出显著的偏向，而在β-arrestin 募集方面则表现出显著的偏向。
