Separate site(s) of action of optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid with opposite pharmacological activities at the GABA receptor complex.
Separate site(s) of action of optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid with opposite pharmacological activities at the GABA receptor complex.
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1-甲基-5-苯基-5-丙基巴比妥酸光学异构体的不同作用位点在 GABA 受体复合物上具有相反的药理活性。
DOI：
10.1016/0014-2999(85)90232-8
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发表时间：
1985
影响因子：
5
通讯作者：
Thyagarajan,R
中科院分区：
文献类型：
--
作者：
Ticku,MK;Rastogi,SK;Thyagarajan,R
本文研究了1-甲基-5-苯基-5-丙基巴比妥酸（MPPB）光学异构体的行为特征及其与GABA受体复合物上致惊剂结合位点的相互作用。R（−）-MPPB产生剂量相关的翻正反射丧失，而S（+）MPPB以剂量依赖性方式产生惊厥。亚惊厥剂量的S（+）MPPB与亚有效剂量的印防己毒素是促惊厥的。S（+）MPPB诱发的癫痫发作可被R（-）MPPB和戊巴比妥阻断。相反，S（+）MPPB不能阻断R（-）MPPB或戊巴比妥引起的翻正反射丧失。S（+）MPPB竞争性抑制[35 S]叔丁基双环硫代磷酸酯（TBPS）（一种与寡聚GABA受体复合物上印防己毒素位点结合的配体）与大鼠脑细胞膜的结合，而R（-）MPPB则非竞争性抑制。因此，具有相反药理作用的MPPB的光学异构体与GABA受体复合物的惊厥（TBPS）位点的相互作用不同。这些结果表明，致惊厥S（+）MPPB和抗惊厥R（-）MPPB可能分别通过作用于GABA受体复合物的致惊厥和抗惊厥位点而产生其行为效应。
The behavioral profile of the optical isomers of 1-methyl-5-phenyl-5-propylbarbituric acid (MPPB) and their interaction with the convulsant binding site at the GABA receptor complex were investigated. R(−)-MPPB produced dose-related loss of righting reflex, whereas S(+)MPPB produced convulsions in a dose-dependent manner. Subconvulsive doses of S(+)MPPB were proconvulsant with a subeffective dose of picrotoxin. S(+)MPPB-induced seizures were blocked by R(−)MPPB and pentobarbital. In contrast, S(+)MPPB did not block the loss of righting reflex produced by R(−)MPPB or pentobarbital. S(+)MPPB inhibited the binding of [35S]t-butylbicyclophosphorothionate (TBPS), a ligand that binds to the picrotoxin site on the oligomeric GABA receptor complex, to rat brain membranes competitively, whereas R(−)MPPB inhibited it noncompetitively. Thus, the optical isomer of MPPB, which have opposite pharmacological effects, interact differently with the convulsant (TBPS) site at the GABA receptor complex. These results suggest that the convulsant S(+)MPPB and the depressant R(−)MPPB may produce their behavioral effects by acting via convulsant and anticonvulsant sites, respectively, at the GABA receptor complex.