Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies
Effect of Substitution on the Aniline Moiety of the GPR88 Agonist 2-PCCA: Synthesis, Structure-Activity Relationships, and Molecular Modeling Studies
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DOI：
10.1021/acschemneuro.6b00182
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发表时间：
2016-10-01
影响因子：
5
通讯作者：
Blough, Bruce E.
中科院分区：
文献类型：
--
作者：
Jin, Chunyang;Decker, Ann M.;Blough, Bruce E.
GPR 88是一种在纹状体中丰富表达的孤儿受体，与许多基底神经节相关疾病有关。为了阐明GPR 88的功能，需要适合于CNS研究的体内探针。我们先前报道2-PCCA能够通过G α（i）偶联途径调节GPR 88介导的cAMP产生。早期的构效关系（SAR）研究表明，2-PCCA的苯胺部分是一个合适的位置进行各种修饰。为了阐明这一区域的结构要求，我们设计并合成了一系列在苯胺部分的苯环上具有各种取代基的类似物。几种化合物（例如，5 j，5 o）显示出改善的或相当的效力，但具有比2-PCCA（clogP 6.19）更低的亲脂性。这些化合物为进一步优化探针GPR 88的体内功能提供了基础。计算研究证实了SAR趋势，并支持联苯环上的4 '-取代基通过大部分疏水结合位点退出细胞外环的观点。
GPR88, an orphan receptor richly expressed in the striatum, is implicated in a number of basal ganglia-associated disorders. In order to elucidate the functions of GPR88, an in vivo probe appropriate for CNS investigation is required. We previously reported that 2-PCCA was able to modulate GPR88-mediated cAMP production through a G alpha(i)-coupled pathway. Early structure-activity relationship (SAR) studies suggested that the aniline moiety of 2-PCCA is a suitable site for diverse modifications. Aimed at elucidating structural requirements in this region, we have designed and synthesized a series of analogues bearing a variety of substituents at the phenyl ring of the aniline moiety. Several compounds (e.g., 5j, 5o) showed improved or comparable potency, but have lower lipophilicity than 2-PCCA (clogP 6.19). These compounds provide the basis for further optimization to probe GPR88 in vivo functions. Computational studies confirmed the SAR trends and supported the notion that 4'-substituents on the biphenyl ring exit through a largely hydrophobic binding site to the extracellular loop.