Alkyl-substituted thiolo-, thiono-, and dithio-gamma-butyrolactones: new classes of convulsant and anticonvulsant agents.
Alkyl-substituted thiolo-, thiono-, and dithio-gamma-butyrolactones: new classes of convulsant and anticonvulsant agents.
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烷基取代的硫代-、硫代-和二硫代-γ-丁内酯：新型惊厥药和抗惊厥药。
DOI：
10.1021/jm00160a032
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发表时间：
1986
影响因子：
7.3
通讯作者：
Covey,DF
中科院分区：
文献类型：
--
作者：
Levine,JA;Ferrendelli,JA;Covey,DF
以α-乙基-α-甲基-γ-丁内酯、β-乙基-β-甲基-γ-丁内酯和双甲-γ-丁内酯为原料，合成了一系列具有神经药理活性的含硫同系物。内酯用苄硫醇阴离子处理形成4-（苄硫基）丁酸，其在用三氟乙酸处理时环化产生硫代内酯。分别用Lawesson试剂或五硫化二磷处理相应的内酯，制备了硫代内酯和二硫代内酯。正如先前对内酯所观察到的，β-取代和β-取代同系物是引起小鼠全身阵挛性和强直性癫痫发作的强效惊厥剂。β-取代同系物对戊四唑诱导的小鼠癫痫发作有抑制作用。α-乙基-α-甲硫基-γ-丁内酯显示出比同类α-乙基-α-甲基-γ-丁内酯的效力增加，并且另外，对最大电休克发作有效。在任何情况下，惊厥药转化为抗惊厥药，反之亦然，通过硫对氧的取代。烷基取代的丁内酯（GBL）是已知的神经活性剂，表现出惊厥或抗惊厥活性依赖于其取代模式。1-5β-取代的GBL可有效抑制实验动物中戊四唑（PTZ）诱导的癫痫发作，而β-和β-取代的GBL可引起惊厥性癫痫发作，其可被有效对抗癫痫小发作的药物如乙琥胺（ESM）以及β-取代的GBL阻断.
A series of sulfur-containing congeners have been prepared from a-ethyl-a-methyl-7-butyrolactone,/3-ethyl-/3-methyl-7-butyrolactone, and ŦŦ dd-tetramethyl-y-butyrolactone as potential neuropharmacologic agents. The lactones were treated with benzyl mercaptide anion to form 4-(benzylthio) butyric acid, which, on treatment with trifluoroacetic acid, cyclized to yield thiololactones. The thiono-and dithiolactones were prepared by treating the corresponding lactones either with Lawesson’s reagent or with phosphoms pentasulfide, respectively. As had been observed previously for the lactones, the/3-substituted and,/3-substituted congeners were potent convulsants that caused generalized clonic and tonic seizures in mice. The Ŧ-substituted congeners were effective in inhibiting pentylenetetrazole-induced seizures in mice. Ŧ-Ethyl-a-methylthiolo-y-butyrolactone showed an increase in potency over the congeneric a-ethyl-a-methyl-7-butyrolactone and, additionally, was effective against maximal electroshock seizures. In no cases was a convulsant converted to an anticonvulsant or vice versa by sulfur-for-oxygensubstitution.Alkyl-substituted-butyrolactones (GBLs) are known to be neuropharmacologically active agents that exhibit either convulsant or anticonvulsant activities dependent on their substitution pattern. 1-5 Ŧ-Substituted GBLs are effective in inhibiting pentylenetetrazole (PTZ)-induced seizures in experimental animals, whereas ß-and, ß-substituted GBLs cause convulsive seizures that can be blocked by drugs which are effective against petit mal seizures, such as ethosuximide (ESM), as well as by Ŧ-substituted GBLs.