Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D-4 Receptor Agonists with High Subtype Selectivity

Pirzer Anna S.; Lasch Roman; Friedrich Heike; Huebner Harald; Gmeiner Peter; Heinrich Markus R.

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Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D-4 Receptor Agonists with High Subtype Selectivity

机译：苄基苯脑血红素肼：一种化学驱动的方法，导致G蛋白质偏置的多巴胺D-4受体激动剂，具有高亚型选择性

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Many subtype-selective dopamine receptor ligands developed for the D-2-D-4 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 K-i(D-4.4) = 0.25 nM, D-2L/D-4.4 = 320, D-3/D-4.4 = 710 for APH199 (17)] can be obtained by choosing a relatively large and conformationally flexible 1-benzyl-1-phenylsemicarbazide substructure to fill the EBP. The novel chemotype APH199 (17) was found to act as a full agonist at the D-4 receptor showing significant bias toward G protein activation over beta-arrestin recruitment in comparison to quinpirole.

机译：为D-2-D-4系列开发的许多亚型选择性多巴胺受体配体掺入1-芳基哌嗪衍生的主要识别基序，其通过脂族连接到含有延伸的受体的延伸粘合口袋（EBP）的亲脂部分可变长度的链接器。新型多巴胺受体配体的评价现在表明，高度亚型 - 选择性配体[至ki（d-4.4）= 0.25nm，d-2l / d-4.4 = 320，d-3 / d-4.4 = 710 对于APH199（17）]可以通过选择相对较大且构象的柔性的1-苄基-1-苯基杀菌伯鸟副结构来获得以填充EBP。发现新型趋化型APH199（17）作为D-4受体的全激动剂，显示出与喹啉相比，β-Arcketin募集的G蛋白激活显着偏差。

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《Journal of Medicinal Chemistry》 |2019年第21期|共22页
作者
Pirzer Anna S.; Lasch Roman; Friedrich Heike; Huebner Harald; Gmeiner Peter; Heinrich Markus R.;
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Friedrich Alexander Univ Erlangen Nurnberg Dept Chem &

Pharm Med Chem Nikolaus Fiebiger Str 10 D-91058 Erlangen Germany;

Friedrich Alexander Univ Erlangen Nurnberg Dept Chem &

Pharm Med Chem Nikolaus Fiebiger Str 10 D-91058 Erlangen Germany;

Friedrich Alexander Univ Erlangen Nurnberg Dept Chem &

Pharm Med Chem Nikolaus Fiebiger Str 10 D-91058 Erlangen Germany;

Friedrich Alexander Univ Erlangen Nurnberg Dept Chem &

Pharm Med Chem Nikolaus Fiebiger Str 10 D-91058 Erlangen Germany;

Friedrich Alexander Univ Erlangen Nurnberg Dept Chem &

Pharm Med Chem Nikolaus Fiebiger Str 10 D-91058 Erlangen Germany;

Friedrich Alexander Univ Erlangen Nurnberg Dept Chem &

Pharm Med Chem Nikolaus Fiebiger Str 10 D-91058 Erlangen Germany;

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中图分类药学;
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1. Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D-4 Receptor Agonists with High Subtype Selectivity [J] . Pirzer Anna S., Lasch Roman, Friedrich Heike, Journal of Medicinal Chemistry . 2019,第21期

机译：苄基苯脑血红素肼：一种化学驱动的方法，导致G蛋白质偏置的多巴胺D-4受体激动剂，具有高亚型选择性
2. A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts [J] . Bingjie Zhang, Simeng Zhao, Dehua Yang, ACS Central Science . 2020,第2期

机译：用于筛选草药提取物的G蛋白偶位受体的新型G蛋白质偏置和亚型选择性激动剂
3. Correction to “A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts” [J] . Bingjie Zhang, Simeng Zhao, Dehua Yang, ACS Central Science . 2020,第5期

机译：校正“从筛选草药提取物发现的G蛋白偶联受体的新型G蛋白质偏置和亚型选择性激动剂”
4. Design Strategies to Produce Receptor Subtype Selective Peptide Agonists and Antagonists for Melanocortie Receptor System [C] . Dhanasekaran Muthu, Robert Soto, Mieying Cai American Peptide Symposium . 2011

机译：制作受体亚型选择性肽激动剂和拮抗剂的设计策略 - Melanocortie受体系统
5. Effector selective intrinsic activity of novel dopamine agonists at the D-2 dopamine receptor. [D] . Smith, Hilary Pamela. 1996

机译：新型多巴胺激动剂对D-2多巴胺受体的效应器选择性内在活性。
6. Structure-Activity Investigation of a G Protein-Biased Agonist Reveals Molecular Determinants for Biased Signaling of the D2 Dopamine Receptor [O] . Lani S. Chun, Rakesh H. Vekariya, R. Benjamin Free, 2018

机译：G蛋白偏激激动剂的结构活性研究揭示了D2多巴胺受体偏向信号的分子决定簇。
7. A Novel G Protein-Biased and Subtype-Selective Agonist for a G Protein-Coupled Receptor Discovered from Screening Herbal Extracts [O] . Bingjie Zhang, Simeng Zhao, Dehua Yang, 2020

机译：用于筛选草药提取物的G蛋白偶位受体的新型G蛋白质偏置和亚型选择性激动剂

Benzyl Phenylsemicarbazides: A Chemistry-Driven Approach Leading to G Protein-Biased Dopamine D-4 Receptor Agonists with High Subtype Selectivity

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