Structure-Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H- chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational Circular Dichroism Spectroscopy in Combination with ab Initio Hartree-Fock Calculations
Structure-Activity Relationship Study of Selective Excitatory Amino Acid Transporter Subtype 1 (EAAT1) Inhibitor 2-Amino-4-(4-methoxyphenyl)-7-(naphthalen-1-yl)-5-oxo-5,6,7,8-tetrahydro-4H- chromene-3-carbonitrile (UCPH-101) and Absolute Configurational Assignment Using Infrared and Vibrational Circular Dichroism Spectroscopy in Combination with ab Initio Hartree-Fock Calculations
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DOI：
10.1021/jm300345z
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发表时间：
2012-06-14
影响因子：
7.3
通讯作者：
Bunch, Lennart
中科院分区：
文献类型：
--
作者：
Huynh, Tri H. V.;Shim, Irene;Bunch, Lennart
兴奋性氨基酸转运体（EAATs）在哺乳动物中枢神经系统中调节神经递质谷氨酸的突触浓度起着重要作用。迄今为止，已经鉴定出五种亚型，在人类中命名为EAAT 1 -5，在啮齿动物中分别命名为GLAST、GLT-1、EAAC 1、EAAT 4和EAAT 5。在本文中，我们提出了七个7-N-取代类似物的UCPH-101/102的设计，合成和药理学评价。Anatomic 9在微摩尔范围内抑制EAAT 1（IC 50值20 μ M），而类似物8和10是无活性的（IC 50值>100 μ M）。用HPLC分离了11 a/11 b和12 a/12 b两对非对映异构体，用VCD技术结合从头算Hartree-Fock方法确定了它们的绝对构型。类似物11 a（RS-异构体）和12 b（RR-异构体）抑制EAAT 1（IC 50值分别为5.5和3.8 μ M），而类似物11 b（SS-异构体）和12 a（SR-异构体）未能抑制EAAT 1摄取（IC 50，值>300 μ M）。
The excitatory amino acid transporters (EAATs) play essential roles in regulating the synaptic concentration of the neurotransmitter glutamate in the mammalian central nervous system. To date, five subtypes have been identified, named EAAT1-5 in humans, and GLAST, GLT-1, EAAC1, EAAT4, and EAAT5 in rodents, respectively. In this paper, we present the design, synthesis, and pharmacological evaluation of seven 7-N-substituted analogues of UCPH-101/102. Analogue 9 inhibited EAAT1 in the micromolar range (IC50 value 20 mu M), whereas analogues 8 and 10 were inactive (IC50 values >100 mu M). The diastereorneric pairs 11a/11b and 12a/12b were separated by HPLC and the absolute configuration assigned by VCD technique in combination with ab initio Hartree-Fock calculations. Analogues 11a (RS-isomer) and 12b (RR-isomer) inhibited EAAT1 (IC50 values 5.5 and 3.8 mu M, respectively), whereas analogues 11b (SS-isomer) and 12a (SR-isomer) failed to inhibit EAAT1 uptake (IC50, values >300 mu M).