Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists.
Design and synthesis of enantiomers of 3,5-dinitro-o-tyrosine: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptor antagonists.
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DOI：
10.1021/jm970276q
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发表时间：
1998-03
影响因子：
7.3
通讯作者：
G. Sun;M. Slavica;N. Uretsky;L. Wallace;G. Shams;D. M. Weinstein;J. Miller;D. Miller
中科院分区：
文献类型：
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作者：
G. Sun;M. Slavica;N. Uretsky;L. Wallace;G. Shams;D. M. Weinstein;J. Miller;D. Miller
3,5-二硝基-o-酪氨酸（6a,b）的R-和s -异构体已通过化学酶合成合成，并显示与α -氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA, 3）受体结合的差异。这些邻酪氨酸类似物的酚类官能团被设计为谷氨酸γ -羧基的生物等异构体。3,5-二硝基-o-酪氨酸（6b）的s -异构体抑制[3H]AMPA结合的能力是r -异构体（6a）的6.5倍，IC50值分别为13 +/- 7和84 +/- 26微米。酚基团对结合亲和力很重要，因为甲氧基化合物7在抑制AMPA结合方面不如酚类化合物6有效。由于n -乙酰基类似物15和N-t-BOC化合物16和17对AMPA受体的亲和力非常低，因此游离氨基也被证明是重要的。AMPA受体功能测试表明，邻酪氨酸类似物具有拮抗剂作用，s -异构体6b （IC50 = 630 +/- 140 microM）比外消旋体6 （IC50 = 730 +/- 88 microM）更有效，而r -异构体6a在1 mM浓度下无活性，这与s -异构体比r -异构体具有更高的结合亲和力是一致的。
The R- and S-isomers of 3,5-dinitro-o-tyrosine (6a,b) have been synthesized through the use of chemoenzymatic synthesis and shown to bind differentially with the alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA, 3) receptors. The phenolic functional group of these o-tyrosine analogues was designed to act as a bioisostere of the gamma-carboxyl group of glutamate. The S-isomer of 3,5-dinitro-o-tyrosine (6b) was 6.5 times more potent than the R-isomer (6a) in inhibiting [3H]AMPA binding with IC50 values of 13 +/- 7 and 84 +/- 26 microM, respectively. The phenolic group was important for binding affinity since the methoxy compound 7 was less potent than the phenolic compound 6 in inhibiting the binding of AMPA. The free amino group was also shown to be important since the N-acetyl analogue 15 and the N-t-BOC compounds 16 and 17 exhibited very low affinity for the AMPA receptors. AMPA receptor functional tests showed that the o-tyrosine analogues are antagonists and that the S-isomer 6b (IC50 = 630 +/- 140 microM) was more potent than the racemate 6 (IC50 = 730 +/- 88 microM) while the R-isomer 6a was inactive up to 1 mM concentration, which is consistent with the S-isomer having higher binding affinity than the R-isomer.