Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.
Synthesis of novel 5-substituted-2-aminotetralin analogs: 5-HT1A and 5-HT7 G protein-coupled receptor affinity, 3D-QSAR and molecular modeling.
复制标题
新型 5-取代-2-氨基四氢化萘类似物的合成：5-HT1A 和 5-HT7 G 蛋白偶联受体亲和力、3D-QSAR 和分子建模。
DOI：
10.1016/j.bmc.2019.115262
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发表时间：
2020
影响因子：
3.5
通讯作者：
Booth,RaymondG
中科院分区：
文献类型：
--
作者：
Perry,CharlesK;Casey,AustenB;Felsing,DanielE;Vemula,Rajender;Zaka,Mehreen;Herrington,NoahB;Cui,Meng;Kellogg,GlenE;Canal,ClintonE;Booth,RaymondG
5-HT7G蛋白偶联受体(GPCR5-HT7G)是多种中枢和外周适应症的药物治疗靶点，尽管目前还没有批准的药物可以选择性地结合5-HT7。我们以前曾报道过一种基于5-取代-N，N-disubstituted-1，2，3，4-tetrahydronaphthalen-2-amine(5-取代-2-氨基四胺，5-SAT)支架的铅类似物在5-HT7GPCR上具有高亲和力，并可以治疗小鼠模型中的自闭症症状；随后，在5-HT1AGPCR上发现该铅具有高亲和力。在这里，我们报道了新的5-SAT类似物的合成，以建立人类5-HT7受体的三维定量结构-亲和力关系(3D-QSAR)，以与在高度同源的5-HT1A受体上的类似研究进行比较。我们报道了35个新的5-≤配体，一些在5-HT7+或5-HT1A受体上具有非常高的亲和力(KI-HT1)和立体选择性，一些在5-HT7上具有适度的选择性(高达12倍)，以及一些在5-HT1A受体上具有高选择性(高达40倍)的配体。3D-QSAR结果表明，与5-HT1A受体相比，C(5)位的空间扩展提高了5-HT7的选择性，而手性C(2)-氨基位置的空间和疏水扩展提高了5-HT1A的选择性。在硅受体同源建模研究中，辅以分子动力学模拟和结合自由能计算，对实验确定的受体选择性和立体选择性亲和力的结果进行了合理化。这些研究的数据表明，先前被证明在神经发育和神经精神障碍的啮齿动物范例中安全有效的5-SAT化学型，可以通过结构修饰来优化与5-HT7vs的亲和力。5-HT1AGPCRs，可能是成功的临床翻译所必需的。
The serotonin 5-HT7G protein-coupled receptor (GPCR) is a proposed pharmacotherapeutic target for a variety of central and peripheral indications, albeit, there are no approved drugs selective for binding 5-HT7. We previously reported that a lead analog based on the 5-substituted-N,N-disubstituted-1,2,3,4-tetrahydronaphthalen-2-amine (5-substituted-2-aminotetralin, 5-SAT) scaffold binds with high affinity at the 5-HT7GPCR, and can treat symptoms of autism in mouse models; subsequently, the lead was found to have high affinity at the 5-HT1AGPCR. Herein, we report the synthesis of novel 5-SAT analogs to develop a 3-dimensional quantitative structure—affinity relationship (3D-QSAR) at the human 5-HT7receptor for comparison with similar studies at the highly homologous 5-HT1Areceptor. We report 35 new 5-SAT ligands, some with very high affinity (Ki≤ 1 nM) and stereoselectivity at 5-HT7+ or 5-HT1Areceptors, several with modest selectivity (up to 12-fold) for binding at 5-HT7, and, several ligands with high selectivity (up to 40-fold) at the 5-HT1Areceptor. 3D-QSAR results indicate that steric extensions at the C(5)-position improve selectivity for the 5-HT7over 5-HT1Areceptor, while steric and hydrophobic extensions at the chiral C(2)-amino position impart 5-HT1Aselectivity.In silicoreceptor homology modeling studies, supplemented with molecular dynamics simulations and binding free energy calculations, were used to rationalize experimentally-determined receptor selectivity and stereoselective affinity results. The data from these studies indicate that the 5-SAT chemotype, previously shown to be safe and efficacious in rodent paradigms of neurodevelopmental and neuropsychiatric disorders, is amenable to structural modification to optimize affinity at serotonin 5-HT7vs. 5-HT1AGPCRs, as may be required for successful clinical translation.