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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests.
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Galmic, a nonpeptide galanin receptor agonist, affects behaviors in seizure, pain, and forced-swim tests.

机译：Galmic是一种非肽甘丙肽受体激动剂，会影响癫痫发作，疼痛和强迫游泳测试中的行为。

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The pharmacological exploitation of the galanin receptors as drug targets for treatment of epilepsy, depression, and pain has been hampered by the lack of workable compounds for medicinal chemists from random screening of large chemical libraries. The present work uses the tripeptidomimetic galnon and displays its presumed pharmacophores on a rigid molecular scaffold. The scaffold is related to marine natural products and presents three functional groups near one another in space, in a manner reminiscent of a protein surface. An active compound, Galmic, was identified from a small synthetic library and tested in vitro and in vivo for its affinity and efficacy at galanin receptors. Galmic has micromolar affinity for GalR1 receptors (Ki = 34.2 microM) and virtually no affinity for GalR2 receptors. In vitro, Galmic, like galanin, suppresses long-term potentiation in the dentate gyrus; it blocks status epilepticus when injected intrahippocampally or administered i.p. Galmic applied i.p. shows antidepressant-like effects in the forced-swim test, and it is a potent inhibitor of flinching behavior in the inflammatory pain model induced by formalin injection. These data further implicate brain and spinal cord galanin receptors as drug targets and provide an example of a systemically active compound based on a scaffold that mimics protein surfaces.
机译：甘丙肽受体作为治疗癫痫，抑郁和疼痛的药物靶点在药理学上的应用受到了从大型化学文库的随机筛选中缺乏可用于药物化学家使用的化合物的阻碍。目前的工作使用三肽模拟加仑，并在刚性分子支架上展示其推测的药效基团。该支架与海洋天然产物有关，并且在空间上彼此呈递三个官能团，其方式使人联想到蛋白质表面。从一个小的合成文库中鉴定了一种活性化合物Galmic，并在体内和体外测试了其对甘丙肽受体的亲和力和功效。 Galmic对GalR1受体具有微摩尔亲和力（Ki = 34.2 microM），而对GalR2受体几乎没有亲和力。在体外，Galmic像甘丙肽一样，能抑制齿状回的长期增强。当海马内注射或腹膜内注射时，它可以阻止癫痫持续状态。 Galmic适用于i.p.在强迫游泳试验中显示出类似抗抑郁药的作用，在福尔马林注射液诱发的炎性疼痛模型中，它是一种有效的退缩行为抑制剂。这些数据进一步暗示脑和脊髓甘丙肽受体作为药物靶标，并提供了基于模仿蛋白质表面的支架的全身活性化合物的实例。

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