Structure--activity studies for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptors: acidic hydroxyphenylalanines.
Structure--activity studies for alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid receptors: acidic hydroxyphenylalanines.
复制标题
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸受体的结构-活性研究：酸性羟基苯丙氨酸。
DOI：
10.1021/jm950028z
复制
发表时间：
1997
影响因子：
7.3
通讯作者：
Danthi,SN
中科院分区：
文献类型：
--
作者：
Hill,RA;Wallace,LJ;Miller,DD;Weinstein,DM;Shams,G;Tai,H;Layer,RT;Willins,D;Uretsky,NJ;Danthi,SN
α-氨基-3-羟基-5-甲基-4-异恶唑丙酸（AMPA）受体拮抗剂可能具有作为精神药物的治疗潜力。制备了一系列单硝基-和二硝基-2-和3-羟基苯丙氨酸，并将其活性与威拉丁、5-硝基威拉丁、AMPA和2,4,5-三羟基苯丙氨酸（6-羟基多巴）进行比较，作为大鼠脑匀浆中特异性[3H]AMPA和[3H]红藻氨酸结合的抑制剂。最活跃的化合物是高酸性（pKa3−4），即2-羟基-3,5-二硝基-dl-苯丙氨酸（13；[3H]AMPA IC50≈25 μM）和3-羟基-2,4-二硝基-dl-苯丙氨酸（19；[3H]AMPA IC50≈5 μM）。另外两种二硝基-3-羟基苯丙氨酸和3,5-二硝基-dl-酪氨酸的活性要低得多。各种酸性较低的单硝基羟基苯丙氨酸的活性也较低或无活性，2-和3-羟基苯丙氨酸（邻位和间位酪氨酸）也无活性。化合物 13 和 19,dl-willardiine (pKa9.3, [3H]AMPA IC50= 2 μM) 和 5-硝基-dl-willardiine (pKa6.4, [3H]AMPA IC50= 0.2 μM) 在结合研究中显示出 AMPA ≫ 红藻氨酸选择性。在大鼠海马神经末梢 AMPA 诱发的去甲肾上腺素释放测定中，化合物 19 是一种 AMPA 样激动剂，但 13 是一种拮抗剂。此外，注射到大鼠腹侧苍白球中的化合物13会拮抗全身性安非他明引起的运动活性。
Antagonists of α-amino-3-hydroxy-5-methyl-4-isoxazolepropanoic acid (AMPA) receptors may have therapeutic potential as psychotropic agents. A series of mononitro- and dinitro-2- and 3-hydroxyphenylalanines was prepared, and their activity compared with willardiine, 5-nitrowillardiine, AMPA, and 2,4,5-trihydroxyphenylalanine (6-hydroxydopa) as inhibitors of specific [3H]AMPA and [3H]kainate binding in rat brain homogenates. The most active compounds were highly acidic (pKa3−4), namely, 2-hydroxy-3,5-dinitro-dl-phenylalanine (13; [3H]AMPA IC50≈ 25 μM) and 3-hydroxy-2,4-dinitro-dl-phenylalanine (19; [3H]AMPA IC50≈ 5 μM). Two other dinitro-3-hydroxyphenylalanines, and 3,5-dinitro-dl-tyrosine, were considerably less active. Various mononitrohydroxyphenylalanines, which are less acidic, were also less active or inactive, and 2- and 3-hydroxyphenylalanine (o- andm-tyrosine) were inactive. Compounds13and19,dl-willardiine (pKa9.3, [3H]AMPA IC50= 2 μM), and 5-nitro-dl-willardiine (pKa6.4, [3H]AMPA IC50= 0.2 μM) displayed AMPA ≫ kainate selectivity in binding studies. Compound19was an AMPA-like agonist, but13was an antagonist in an AMPA-evoked norepinephrine release assay in rat hippocampal nerve endings. Also, compound13injected into the rat ventral pallidum antagonized the locomotor activity elicited by systemic amphetamine.