Jane D E, Hoo K, Kamboj R, Deverill M, Bleakman D, Mandelzys A
Department of Pharmacology, School of Medical Sciences, University of Bristol, U.K.
J Med Chem. 1997 Oct 24;40(22):3645-50. doi: 10.1021/jm9702387.
Both willardiine and azawillardiine analogs (18-28) have been reported to be potent and selective agonists for either AMPA or kainate receptors. We report here the novel synthesis and pharmacological characterization of a range of willardiine (18-23) and 6-azawillardiine (24-28) analogs on cells individually expressing human homomeric hGluR1, hGluR2, hGluR4, or hGluR5 receptors. Reaction of the sodium salts of substituted uracils (7-12) or 6-azauracils (13-16) with (S)-3-[(tert-butoxycarbonyl)amino]oxetan-2-one (17) in dry DMF, subsequent deprotection in TFA, and purification by ion-exchange chromatography gave mainly the willardiine analog in which alkylation took place on N1 of the uracil ring. We have investigated the subtype selectivity of these compounds by examining their binding affinity for homomeric hGluR1, -2, -4, or -5 (and hGluR6 in the case of 5-iodowillardiine (22)). From this study we have demonstrated that 22 has high affinity for hGluR5 and, compared to kainate, displays excellent selectivity for this receptor over both the AMPA receptor subtypes and the homomeric kainate receptor, hGluR6. 5-Fluorowillardiine (19) has higher affinity than AMPA for both homomeric hGluR1 and hGluR2 and compared to AMPA displays greater selectivity for AMPA receptor subtypes over the kainate receptor, hGluR5. Some structural features required for optimal activity at homomeric AMPA or kainate receptor subtypes have also been identified. It would appear that quite large lipophilic substituents at the 5-position of the uracil ring not only are accommodated by hGluR5 receptors but also lead to enhanced affinity for these receptors. In contrast to this, for optimal binding affinity to hGluR1, -2, or -4, smaller, electron-withdrawing substituents are required. For optimal activity at hGluR4 receptors a 6-aza-substituted willardiine is favored. The subtype-selective compounds described here are likely to be useful tools to probe the distribution and the physiological roles of the various glutamate receptor subunits in the central nervous system.
据报道，威拉地丁及其氮杂威拉地丁类似物（18 - 28）对AMPA或海人藻酸受体具有强效且选择性的激动作用。我们在此报告了一系列威拉地丁（18 - 23）和6 - 氮杂威拉地丁（24 - 28）类似物在分别表达人同源性hGluR1、hGluR2、hGluR4或hGluR5受体的细胞上的新合成方法及药理学特性。取代尿嘧啶（7 - 12）或6 - 氮杂尿嘧啶（13 - 16）的钠盐与（S）-3 - [（叔丁氧羰基）氨基]氧杂环丁烷 - 2 - 酮（17）在干燥的N,N - 二甲基甲酰胺中反应，随后在三氟乙酸中脱保护，并通过离子交换色谱法纯化，主要得到在尿嘧啶环的N1位发生烷基化的威拉地丁类似物。我们通过检测这些化合物对同源性hGluR1、-2、-4或-5（对于5 - 碘威拉地丁（22）则检测对hGluR6）的结合亲和力，研究了这些化合物的亚型选择性。通过这项研究我们证明，22对hGluR5具有高亲和力，并且与海人藻酸相比，对该受体显示出优于AMPA受体亚型和同源性海人藻酸受体hGluR6的出色选择性。5 - 氟威拉地丁（19）对同源性hGluR1和hGluR2的亲和力均高于AMPA，并且与AMPA相比，对AMPA受体亚型显示出比对海人藻酸受体hGluR5更大的选择性。还确定了在同源性AMPA或海人藻酸受体亚型上实现最佳活性所需的一些结构特征。似乎尿嘧啶环5位上相当大的亲脂性取代基不仅能被hGluR5受体容纳，还能增强对这些受体的亲和力。与此相反，为了与hGluR1、-2或-4实现最佳结合亲和力，则需要较小的吸电子取代基。对于在hGluR4受体上实现最佳活性，6 - 氮杂取代的威拉地丁更受青睐。本文所述的亚型选择性化合物可能是用于探究中枢神经系统中各种谷氨酸受体亚基的分布和生理作用的有用工具。
