Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D2R Agonists
Hydroxy-Substituted Heteroarylpiperazines: Novel Scaffolds for β-Arrestin-Biased D2R Agonists
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DOI：
10.1021/acs.jmedchem.7b00363
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发表时间：
2017-06-08
影响因子：
7.3
通讯作者：
Gmeiner, Peter
中科院分区：
文献类型：
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作者：
Maennel, Barbara;Dengler, Daniela;Gmeiner, Peter
通过抗精神病药物阿立哌唑与 β(2)-肾上腺素受体激动剂丙卡特罗和 BI-167107 中存在的杂环儿茶酚胺替代物和 BI-167107 (4) 的正式结构杂交，我们设计并合成了一系列具有高多巴胺 D-2 受体 (D2R) 亲和力的新型羟基取代杂芳基哌嗪和杂酰基高哌嗪。与阿立哌唑的弱激动行为相反，这些配体能够有效地模拟多巴胺和阿立哌唑的相互作用。 D2R。这对于活跃状态至关重要，导致招募 beta-arrestin-2。有趣的是，一些配体在 D2R 鸟嘌呤核苷酸交换实验中显示出相当低的内在活性。因此代表偏向激动剂，有利于 β-arrestin-2 募集而不是经典 G 蛋白激活。配体的激动特性基本上是由环内氢键供体的存在驱动的。
By means of a formal structural hybridization of the antipsychotic drug aripiprazole and the heterocyclic catecholamine surrogates present in the beta(2)-adrenoceptor agonists procaterol and BI-167107 (4),, we designed and synthesized a collection of novel hydroxy-substituted heteroarylpiperazines and heteroatylhomopiperazines with high dopamine D-2 receptor (D2R) affinity. In contrast to the weak agonistic behavior of aripiprazole, these ligands are capable of effectively mimicking those interactions of dopamine and the. D2R. that are crucial for an active state, leading to the recruitment of beta-arrestin-2. Interestingly, some ligands show considerably lower intrinsic activity in guanine nucleotide exchange experiments at D2R. and consequently represent biased agonists favoring beta-arrestin-2 recruitment over canonical G protein activation. The ligands' agonistic properties are substantially driven by thepresence of an endocyclic H-bond donor.