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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Anticonulsant activity of a nonpeptide galanin receptor agonist
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Anticonulsant activity of a nonpeptide galanin receptor agonist

机译：非肽甘丙肽受体激动剂的抗惊厥活性

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摘要

Galanin is a neuropeptide with a wide variety of biological functions, including that of a strong endogenous anticonvulsant. No nonpeptide ligands, capable of activating galanin receptors, are available today. Based on known pharmacophores of galanin, a combinatorial library was designed, synthesized, and screened at the rat hippocampal galanin receptor. A low molecular weight galanin receptor agonist, 7-((9-fluorenylmethoxycarbonyl)cy-clohexylalanyllysyl)amino-4-methylcoumarin (galnon) was found to displace ~(125)I-galanin with micromolar affinity at Bowes cellular and rat hippocampal membranes. Autoradiographic binding assay on rat spinal cord sections confirmed the ability of galnon to displace ~(125)I-galanin from its binding sites. Galnon inhibited ade-nylate cyclase activity, suggesting an agonist action at galanin receptors. When injected i.p. galnon reduced the severity and increased the latency of pentylenetetrazole-induced seizures in mice and reversed the proconvulsant effects of the galanin receptor antagonist M35, injected into a lateral ventricle. Intrahippocam-pal injection of galnon also shortened the duration of self-sustaining status epilepticus in rats, confirming its agonist properties in vivo. Pretreatment of rats with antisense peptide nucleic acid targeted to galanin receptor type 1 mRNA abolished the effect of galnon, suggesting mediation of its anticonvulsant properties through this receptor subtype. These findings introduce a system-ically active nonpeptide galanin agonist anticonvulsant.
机译：甘丙肽是一种具有多种生物学功能的神经肽，包括强大的内源性抗惊厥药。如今没有能够激活甘丙肽受体的非肽配体。基于甘丙肽的已知药效团，设计，合成并筛选了大鼠海马甘丙肽受体的组合文库。发现低分子量甘丙肽受体激动剂7-（（（9-芴基甲氧基羰基）环己基丙氨酰基赖氨酰）氨基-4-甲基香豆素（galnon）在Bowes细胞和大鼠海马膜上以微摩尔亲和力取代〜（125）I-甘丙肽。对大鼠脊髓切片的放射自显影结合测定证实了加农酮能够从其结合位点置换〜（125）I-甘丙肽。 Galnon抑制了腺苷酸环化酶的活性，提示对甘丙肽受体有激动作用。注射时galnon降低了戊四唑诱导的小鼠癫痫发作的严重程度并增加了潜伏期，并逆转了注入侧脑室的甘丙肽受体拮抗剂M35的惊厥作用。内镜下注射加农酮还可以缩短大鼠自我维持癫痫持续状态的持续时间，从而证实了其在体内的激动剂特性。用针对甘丙肽受体1型mRNA的反义肽核酸对大鼠进行预处理，消除了加农酚的作用，表明通过该受体亚型介导了其抗惊厥特性。这些发现引入了系统活性的非肽甘丙肽激动剂抗惊厥药。

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