Chweh A Y, Swinyard E A, Wolf H H, Kupferberg H J
Epilepsia. 1983 Dec;24(6):668-77. doi: 10.1111/j.1528-1157.1983.tb04629.x.
Five clinically available 1,4-benzodiazepines (BDZs) (chlordiazepoxide, diazepam, oxazepam, nitrazepam, and clonazepam) and four investigational 1,4-BDZs (BDZ I, BDZ II, BDZ III, and BDZ IV) were tested in vivo for minimal neurotoxicity (TD50) and for ability to obtund seizures (ED50) induced by a battery of five well-standardized procedures (maximal electroshock, strychnine, pentylenetetrazol, bicuculline, and picrotoxin). In addition, these BDZs were also tested in vitro as inhibitors of [3H]flunitrazepam binding to BDZ receptors. The results with each of the six in vivo tests were compared with those with the in vitro receptor binding test, and the correlation coefficients (r) were calculated. There was a high correlation between the inhibitor constants (Ki) derived from BDZ binding studies and the TD50 values (r = 0.882) and the pentylenetetrazol ED50 values (r = 0.946). There was also good correlation between ED50 values of BDZs effective by the bicuculline and picrotoxin tests and their Ki values in the BDZ receptor binding studies (r = 0.868 and 0.892, respectively). However, BDZ I, BDZ II, and BDZ IV had Ki values of 1.830, 0.075, and 0.015 microM, respectively, but BDZ I was ineffective in nontoxic doses by the bicuculline and picrotoxin tests, BDZ II by the picrotoxin test, and BDZ IV by the bicuculline test. In contrast, there was no correlation between the BDZs' anticonvulsant potency, determined by either the maximal electroshock or strychnine test, and their inhibitory potency on [3H]flunitrazepam binding to receptor sites. The possible methodological and neurochemical bases for these differences are discussed. These studies indicate that BDZ binding studies can be used to screen BDZs for anticonvulsant activity (selectively for antipentylenetetrazol activity and less selectively for antibicuculline and antipicrotoxin activity). More importantly, they complement the conventional in vivo anticonvulsant threshold tests. Therefore, BDZ binding studies can be used in concert with conventional in vivo procedures for the pharmacological differentiation of candidate antiepileptic BDZs.
对五种临床可用的1,4 - 苯二氮䓬类药物（BDZs）（氯氮卓、地西泮、奥沙西泮、硝西泮和氯硝西泮）以及四种研究用的1,4 - BDZs（BDZ I、BDZ II、BDZ III和BDZ IV）进行了体内最小神经毒性（TD50）测试以及通过一系列五个标准化良好的程序（最大电休克、士的宁、戊四氮、荷包牡丹碱和印防己毒素）诱导的惊厥抑制能力（ED50）测试。此外，还对这些BDZs进行了体外作为[3H]氟硝西泮与BDZ受体结合抑制剂的测试。将六种体内测试中每种测试的结果与体外受体结合测试的结果进行比较，并计算相关系数（r）。源自BDZ结合研究的抑制常数（Ki）与TD50值（r = 0.882）和戊四氮ED50值（r = 0.946）之间存在高度相关性。通过荷包牡丹碱和印防己毒素测试有效的BDZs的ED50值与其在BDZ受体结合研究中的Ki值之间也存在良好相关性（分别为r = 0.868和0.892）。然而，BDZ I、BDZ II和BDZ IV的Ki值分别为1.830、0.075和0.015 microM，但BDZ I在无毒剂量下对荷包牡丹碱和印防己毒素测试无效，BDZ II对印防己毒素测试无效，BDZ IV对荷包牡丹碱测试无效。相反，通过最大电休克或士的宁测试确定的BDZs的抗惊厥效力与其对[3H]氟硝西泮与受体位点结合的抑制效力之间没有相关性。讨论了这些差异可能的方法学和神经化学基础。这些研究表明，BDZ结合研究可用于筛选具有抗惊厥活性的BDZs（对抗戊四氮活性具有选择性，对抗荷包牡丹碱和抗印防己毒素活性的选择性较低）。更重要的是，它们补充了传统的体内抗惊厥阈值测试。因此，BDZ结合研究可与传统的体内程序协同使用，用于候选抗癫痫BDZs的药理学鉴别。
