Bang-Andersen B, Lenz S M, Skjaerbaek N, Søby K K, Hansen H O, Ebert B, Bøgesø K P, Krogsgaard-Larsen P
Research Departments, H. Lundbeck A/S, Copenhagen, Denmark.
J Med Chem. 1997 Aug 29;40(18):2831-42. doi: 10.1021/jm970253b.
A number of 3-isoxazolol bioisosteres, 7a-i, of (S)-glutamic acid (Glu), in which the methyl group of (RS)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid (AMPA, 1) was replaced by different 5-membered heterocyclic rings, were synthesized. Comparative in vitro pharmacological studies on this series of AMPA analogues were performed using receptor binding assays (IC50 values) and the electrophysiological rat cortical slice model (EC50 values). None of these compounds showed detectable affinity for the N-methyl-D-aspartic acid subtype of Glu receptors. Some of the compounds were weak inhibitors of [3H]kainic acid binding. The inhibitory effects on [3H]AMPA binding and agonist potencies at AMPA receptors of 7a-i were strictly dependent on the structure, electrostatic potential, and methyl substitution of the heterocyclic 5-substituent. Thus, while 7a (IC50 = 0.094 microM; EC50 = 2.3 microM) was approximately equipotent with AMPA (IC50 = 0.023 microM; EC50 = 5.4 microM), (RS)-2-amino-3-[3-hydroxy-5-(1H-imidazol-2-yl)isoxazol-4-yl]propio nic acid (7b) (IC50 = 48 microM; EC50 = 550 microM) was some 2 orders of magnitude weaker than AMPA, and (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-imidazol-2-yl)-isoxazol-4 -yl] propionic acid (7c) (IC50 > 100 microM; EC50 > 1000 microM) was inactive. Furthermore, (RS)-2-amino-3-[3-hydroxy-5-(2-methyl-2H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (7i) (IC50 = 0.030 microM; EC50 = 0.92 microM) was more potent than AMPA, whereas its N-1 methyl isomer, (RS)-2-amino-3-[3-hydroxy-5-(1-methyl-1H-tetrazol-5-yl)isoxazol -4-yl] propionic acid (7h) (IC50 = 54 microM; EC50 > 1000 microM) was inactive as an AMPA agonist. A quantitative structure-activity relationship (QSAR) analysis revealed a positive correlation between receptor affinity, electrostatic potential near the nitrogen atom at the "ortho" position of the heterocyclic 5-substituent, and the rotational energy barrier around the bond connecting the two rings. We envisage that a hydrogen bond between the protonated amino group and an ortho-positioned heteroatom of the ring substituent at the 5-position stabilize receptor-active conformations of these AMPA analogues.
合成了一系列（S）-谷氨酸（Glu）的3-异恶唑醇生物电子等排体7a-i，其中（RS）-2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸（AMPA，1）的甲基被不同的五元杂环取代。使用受体结合试验（IC50值）和电生理大鼠皮层切片模型（EC50值）对该系列AMPA类似物进行了体外药理学比较研究。这些化合物均未显示出对Glu受体N-甲基-D-天冬氨酸亚型的可检测亲和力。其中一些化合物是[3H] kainic酸结合的弱抑制剂。7a-i对[3H] AMPA结合的抑制作用和在AMPA受体上的激动剂效力严格取决于杂环5-取代基的结构、静电势和甲基取代情况。因此，虽然7a（IC50 = 0.094 microM；EC50 = 2.3 microM）与AMPA（IC50 = 0.023 microM；EC50 = 5.4 microM）大致等效，但（RS）-2-氨基-3-[3-羟基-5-（1H-咪唑-2-基）异恶唑-4-基]丙酸（7b）（IC50 = 48 microM；EC50 = 550 microM）比AMPA弱约2个数量级，而（RS）-2-氨基-3-[3-羟基-5-（1-甲基-1H-咪唑-2-基）异恶唑-4-基]丙酸（7c）（IC50 > 100 microM；EC50 > 1000 microM）无活性。此外，（RS）-2-氨基-3-[3-羟基-5-（2-甲基-2H-四唑-5-基）异恶唑-4-基]丙酸（7i）（IC50 = 0.030 microM；EC50 = 0.92 microM）比AMPA更有效，而其N-1甲基异构体（RS）-2-氨基-3-[3-羟基-5-（1-甲基-1H-四唑-5-基）异恶唑-4-基]丙酸（7h）（IC50 = 54 microM；EC50 > 1000 microM）作为AMPA激动剂无活性。定量构效关系（QSAR）分析表明，受体亲和力、杂环5-取代基“邻位”氮原子附近的静电势与连接两个环的键周围的旋转能垒之间存在正相关。我们设想，质子化氨基与5-位环取代基的邻位杂原子之间的氢键稳定了这些AMPA类似物的受体活性构象。
