†Department of Chemistry and Center for Neuroscience Research, University at Albany, Albany, New York 12222, United States.
‡Department of Drug Sciences and Products for Health, University of Messina, Viale Annunziata, 98168 Messina, Italy.
ACS Chem Neurosci. 2015 Aug 19;6(8):1371-8. doi: 10.1021/acschemneuro.5b00064. Epub 2015 May 29.
2,3-Benzodiazepines are a well-known group of compounds for their potential antagonism against AMPA receptors. It has been previously reported that the inhibitory effect of 2,3-benzodiazepine derivatives with a 7,8-ethylenedioxy moiety can be enhanced by simply adding a chlorine atom at position 3 of the 4-aminophenyl ring. Here we report that adding a methyl group at position 3 on the 4-aminophenyl ring, termed as BDZ-11-7, can similarly enhance the inhibitory activity, as compared with the unsubstituted one or BDZ-11-2. Our kinetic studies have shown that BDZ-11-7 is a noncompetitive antagonist of GluA2Q homomeric receptors and prefers to inhibit the closed-channel state. However, adding another methyl group at position 5 on the 4-aminophenyl ring, termed as BDZ-11-6, fails to yield extra inhibition on GluA2Q receptors. Instead, BDZ-11-6 exhibits a diminished inhibition of GluA2Q. Site interaction test indicates the two compounds, BDZ-11-6 and BDZ-11-7, bind to the same site on GluA2Q, which is also the binding site for their prototype, BDZ-11-2. Based on the results from this and our earlier studies, we propose that the binding site that accommodates the 4-aminophenyl ring must contain two interactive points, with one preferring polar groups like chlorine and the other preferring nonpolar groups such as a methyl group. Either adding a chlorine or a methyl group may enhance the inhibitory activity of 2,3-benzodiazepine derivatives with a 7,8-ethylenedioxy moiety. Adding any two of the same group on positions 3 and 5 of the 4-aminophenyl ring, however, significantly reduces the interaction between these 2,3-benzodiazepines and their binding site, because one group is always repelled by one interactive point. We predict therefore that adding a chlorine atom at position 3 and a methyl group at position 5 of the 4-aminophenyl ring of 2,3-benzodiazepine derivatives with a 7,8-ethylenedioxy moiety may produce a new compound that is more potent.
2,3-苯并二氮杂䓬是一组众所周知的化合物，因其对 AMPA 受体具有潜在的拮抗作用。先前已有报道表明，在 4-氨基苯基环的 3 位上简单地添加一个氯原子，可以增强具有 7,8-亚乙基二氧基部分的 2,3-苯并二氮䓬衍生物的抑制作用。在这里，我们报告称，在 4-氨基苯基环的 3 位上添加一个甲基，称为 BDZ-11-7，可以与未取代的或 BDZ-11-2 相比，类似地增强抑制活性。我们的动力学研究表明，BDZ-11-7 是 GluA2Q 同型受体的非竞争性拮抗剂，并且更喜欢抑制关闭通道状态。然而，在 4-氨基苯基环的 5 位上再添加一个甲基，称为 BDZ-11-6，则不能对 GluA2Q 受体产生额外的抑制作用。相反，BDZ-11-6 表现出对 GluA2Q 的抑制作用减弱。位点相互作用测试表明，这两种化合物，BDZ-11-6 和 BDZ-11-7，结合到 GluA2Q 的相同位点，该位点也是其原型 BDZ-11-2 的结合位点。基于这一结果和我们之前的研究，我们提出容纳 4-氨基苯基环的结合位点必须包含两个相互作用点，一个点更喜欢氯等极性基团，另一个点更喜欢甲基等非极性基团。在具有 7,8-亚乙基二氧基部分的 2,3-苯并二氮杂䓬衍生物上添加氯或甲基，都可能增强其抑制活性。然而，在 4-氨基苯基环的 3 位和 5 位上添加相同的两个基团，则会显著降低这些 2,3-苯并二氮杂䓬与它们的结合位点之间的相互作用，因为一个基团总是被一个相互作用点排斥。因此，我们预测在具有 7,8-亚乙基二氧基部分的 2,3-苯并二氮杂䓬衍生物的 4-氨基苯基环的 3 位上添加氯原子，在 5 位上添加甲基，可能会产生一种更有效的新化合物。
