Antinociceptive Activities of a-Truxillic Acid and -Truxinic Acid Derivatives
Antinociceptive Activities of a-Truxillic Acid and -Truxinic Acid Derivatives
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α-Truxinic Acid 和 α-Truxinic Acid 衍生物的抗伤害活性
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发表时间：
2006
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通讯作者：
S. Sakurada
中科院分区：
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作者：
Y. Chi;Motoyuki Nakamura;Xi;T. Yoshizawa;Wen;F. Hashimoto;J. Kinjo;T. Nohara;S. Sakurada
我们最近的研究表明，α-曲克酸衍生物的二聚体结构在其抗炎活性的表达中起着重要作用。为了研究结构与抗炎活性之间的关系，合成了α-truxillic acid（1）及其衍生物（2-6），β-truxinic acid（7）及其衍生物（8-10），并在福尔马林试验中评价了它们的抗炎活性。所有化合物对神经源性疼痛反应的活性都很弱或没有活性，但对福尔马林诱导的炎性疼痛反应有显著的活性。α-曲克酸（1）及其衍生物4，4 ′-二羟基-α-曲克酸（2）的抗炎活性最高。此外，α-truxillic acid（1）及其衍生物α-truxillic acid bis（p-nitrophenyl）ester（5）的抗炎活性高于β-truxinic acid（7）及其衍生物（10）。此外，游离羧酸（1，2）表现出比它们的二甲酯（3，4）和双（对硝基苯基）酯（5）更高的活性。这些结果证实了二聚体结构的α-形成和游离羧酸对于抗炎活性的表达也是重要的。另外，4，4 ′-二氯-β-truxinic acid（8）的抗炎活性高于母体化合物7，另外，1，3-二苯甲酰基-2，4-二（4-氯苯基）环丁烷（6）也表现出较强的抗炎活性。这些结果表明，在苯基基团的取代基也是重要的抗炎活性的表达。为了获得有关其活性强度的信息，在福尔马林试验中将2和4，4 ′-二氯代衍生物（6，8）的抗炎活性与吲哚美辛（一种非甾体抗炎药）的抗炎活性进行了比较。结果表明，化合物2、6和8的抗炎活性均强于吲哚美辛。这些结果提示α-曲克酸和β-曲克酸衍生物有可能开发成为一种新型的抗炎药物。
Our recent study demonstrated that the dimeric structure of α-truxillic acid derivatives played an important role in the expression of their anti-inflammatory activities. In the present report, to investigate the correlation between the structure and anti-inflammatory activity, α-truxillic acid (1) and its derivatives (2—6), β-truxinic acid (7) and its derivatives (8—10) were prepared, and their activities were evaluated in the formalin test. All compounds showed only weak or no activities against the neurogenic pain response, but demonstrated significant activities against the inflammatory pain response induced by formalin. The highest anti-inflammatory activities were observed for α-truxillic acid (1) and its derivative 4,4′-dihydroxy-α-truxillic acid (2). In addition, α-truxillic acid (1) and its derivative, α-truxillic acid bis(p-nitrophenyl)ester (5), showed higher anti-inflammatory activities than β-truxinic acid (7) and the corresponding derivative (10). Furthermore, free carboxylic acids (1, 2) showed higher activities than their dimethyl esters (3, 4) and bis(p-nitrophenyl)ester (5). These results confirmed that the α-formation of dimeric structure and the free carboxylic acid were also important for the expression of anti-inflammatory activities. Otherwise, 4,4′-dichloro-β-truxinic acid (8) had higher activity than its parent compound 7; furthermore, 1,3-dibenzoyl-2,4-di(4-chlorophenyl)cyclobutane (6) also showed strong anti-inflammatory activity. These results suggested that substituents in the phenyl groups were also important for the expression of anti-inflammatory activity. In order to gain information about their activity intensity, the anti-inflammatory activities of 2 and 4,4′-dichlorolated derivatives (6, 8) were compared with that of indomethacin (a nonsteroidal anti-inflammatory drug) in the formalin test. As a result, compounds 2, 6 and 8 showed stronger anti-inflammatory activities than indomethacin. These results suggested that α-truxillic acid and β-truxinic acid derivatives might be developed into a new type of anti-inflammatory drug.