Racemic _K‐opioid receptor (KOR) agonist 2‐(3,4‐dichlorophenyl)‐1‐[(4aRS ,8SR ,8aSR )‐8‐(pyrrolidin‐1‐yl)‐3,4,4a,5,6,7,8,8a‐octahydroquinolin‐1(2H )‐yl]ethan‐1‐one ((±)‐4 ) was prepared in a diastereoselective synthesis. The first key step of the synthesis was the diastereoselective hydrogenation of the silyl ether of 1,2,3,4‐tetrahydroquinoin‐8‐ol ((±)‐9 ) to afford cis ,cis‐configured perhydroquinoline derivative (±)‐10 . Removal of the TBDMS protecting group led to a β‐aminoalcohol that reacted with SO₂Cl₂ to form an oxathiazolidine. Nucleophilic substitution with pyrrolidine resulted in the desired cis ,trans‐configured perhydroquinoline upon inversion of the configuration. In order to obtain enantiomerically pure KOR agonists 4 (99.8 % ee ) and ent‐4 (99.0 % ee ), 1,2,3,4‐tetrahydroquinolin‐8‐ols (R )‐8 (99.1 % ee ) and (S )‐8 (98.4 % ee ) were resolved by an enantioselective acetylation catalyzed by Amano lipase PS‐IM. The absolute configuration was determined by CD spectroscopy. The 4aR ,8S ,8aS‐configured enantiomer 4 showed sub‐nanomolar KOR affinity (K _i=0.81 nM), which is more than 200 times higher than the KOR affinity of its enantiomer ent‐4 . In the cAMP assay and the Tango β‐arrestin‐2 recruitment assay, 4 behaved as a KOR agonist. Upon incubation of human macrophages, human dendritic cells, and mouse myeloid immune cells with 4 , the number of cells expressing co‐stimulatory receptor CD86 and proinflammatory cytokines interleukin 6 and tumor necrosis factor α was significantly reduced; this indicates the strong anti‐inflammatory activity of 4 . The anti‐inflammatory effects correlated well with the KOR affinity: (4aR ,8S ,8aS )‐4 was slightly more potent than the racemic mixture (±)‐4 , and the distomer ent‐4 was almost inactive.

中文翻译：

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对映体纯喹啉基 κ-阿片受体激动剂：化学酶合成和药理学评价。

外消旋_K-阿片受体(KOR)激动剂2-(3,4-二氯苯基)-1-[(4a RS ,8 SR ,8a SR )-8-(吡咯烷-1-基)-3,4,4a,5 ,6,7,8,8a-八氢喹啉-1(2 H )-基]乙烷-1-酮((±) -4 )是通过非对映选择性合成制备的。合成的第一个关键步骤是1,2,3,4-四氢醌-8-醇((±)-9 )的甲硅烷基醚的非对映选择性氢化，得到顺式、顺式构型的全氢喹啉衍生物(±) -10。去除 TBDMS 保护基团会产生 β-氨基醇，该醇与 SO ₂ Cl ₂反应形成恶噻唑烷。吡咯烷的亲核取代在构型反转后产生了所需的顺式、反式构型的全氢喹啉。为了获得对映体纯的 KOR 激动剂4 (99.8 % ee ) 和ent ‐ 4 (99.0 % ee )，1,2,3,4-四氢喹啉-8-醇 ( R )‐ 8 (99.1 % ee ) 和 ( S )‐ 8 (98.4 % ee ) 通过天野脂肪酶 PS-IM 催化的对映选择性乙酰化进行解析。通过CD光谱测定绝对构型。4a R , 8 S ,8a S构型的对映体4显示出亚纳摩尔 KOR 亲和力（K _{i =0.81 nM），比其对映}体4的 KOR 亲和力高 200 倍以上。在 cAMP 测定和 Tango β-arrestin-2 招募测定中，4表现为 KOR 激动剂。将人巨噬细胞、人树突状细胞和小鼠骨髓免疫细胞与4一起孵育后，表达共刺激受体 CD86 和促炎细胞因子白细胞介素 6 和肿瘤坏死因子 α 的细胞数量显着减少；这表明4具有很强的抗炎活性。抗炎作用与 KOR 亲和力密切相关：(4a R ,8 S ,8a S )- 4比外消旋混合物 (±)- 4稍强，而反异构体- 4几乎没有活性。