Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands
Design and Synthesis of Bitopic 2-Phenylcyclopropylmethylamine (PCPMA) Derivatives as Selective Dopamine D3 Receptor Ligands
复制标题
作为选择性多巴胺 D3 受体配体的双位 2-苯基环丙基甲胺 (PCPMA) 衍生物的设计与合成
DOI：
10.1021/acs.jmedchem.9b01835
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发表时间：
2020-05-14
影响因子：
7.3
通讯作者：
Cheng, Jianjun
中科院分区：
文献类型：
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作者：
Tan, Liang;Zhou, Qingtong;Cheng, Jianjun
2-苯基环丙基甲胺（PCPMA）类似物已被报道为选择性5-羟色胺2C激动剂。在相同的骨架基础上，我们设计合成了一系列的双拓扑衍生物作为多巴胺D3 R配体。许多这些新化合物显示出对D3 R的高结合亲和力和优异的选择性。化合物（1 R，2 R）-22e及其对映体（1 S，2S）-22e显示出与D3 R相当的结合亲和力，但前者是有效的D3 R激动剂，而后者充当拮抗剂。分子对接研究揭示了不同的结合位姿的PCPMA部分内的正构结合口袋的D3 R，这可能解释了不同的功能配置文件的对映异构体。化合物（1 R，2 R）-30 q显示出对D3 R的高结合亲和力（Ki = 2.2 nM），沿着具有良好的选择性，以及良好的生物利用度和小鼠脑渗透特性。这些结果表明，PCPMA支架可以作为一个特权的胺能GPCR配体的设计支架。
2-Phenylcyclopropylmethylamine (PCPMA) analogues have been reported as selective serotonin 2C agonists. On the basis of the same scaffold, we designed and synthesized a series of bitopic derivatives as dopamine D3R ligands. A number of these new compounds show a high binding affinity for D3R with excellent selectivity. Compound (1R,2R)-22e and its enantiomer (1S,2S)-22e show a comparable binding affinity for the D3R, but the former is a potent D3R agonist, while the latter acts as an antagonist. Molecular docking studies revealed different binding poses of the PCPMA moiety within the orthosteric binding pocket of the D3R, which might explain the different functional profiles of the enantiomers. Compound (1R,2R)-30q shows a high binding affinity for the D3R (K-i = 2.2 nM) along with good selectivity, as well as good bioavailability and brain penetration properties in mice. These results reveal that the PCPMA scaffold may serve as a privileged scaffold for the design of aminergic GPCR ligands.