Perturbation of benzodiazepine receptor binding by pyrazolopyridines involves picrotoxinin/barbiturate receptor sites
Perturbation of benzodiazepine receptor binding by pyrazolopyridines involves picrotoxinin/barbiturate receptor sites
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吡唑并吡啶对苯二氮卓受体结合的干扰涉及印防己毒素/巴比妥酸盐受体位点
DOI：
10.1523/jneurosci.01-05-00471.1981
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发表时间：
1981
影响因子：
2.8
通讯作者：
R. Olsen
中科院分区：
文献类型：
--
作者：
F. Leeb‐Lundberg;A. Snowman;R. Olsen
两种吡唑并吡啶类药物，依唑酯 (SQ20009) 和卡他唑酯 (SQ65396)，可增强 [3H]地西泮与大鼠脑中苯二氮卓受体位点的结合。这种增强是由于亲和力的变化而最大结合力没有变化。戊巴比妥还通过降低 K(D) 来增强 [3H]地西泮结合。戊巴比妥对苯二氮卓结合的最大增强作用略大于依他唑酯诱导的最大增强作用，但依他唑酯的最大浓度不能进一步增加戊巴比妥的最大增强作用。相比之下，γ-氨基丁酸（GABA）对苯二氮卓类药物结合的增强与依他唑酯或戊巴比妥的作用完全相加。 γ-氨基丁酸的增强作用被两种γ-氨基丁酸模拟化合物、咪唑乙酸和4,5,6,7-四氢异恶唑并[5,4-c]吡啶-3-醇(THIP)特异性阻断，这些化合物不会抑制戊巴比妥或依唑酯对地西泮结合的增强作用。 1 至 10 μM 印防己毒素可以竞争性阻断依唑酯和戊巴比妥的作用，但不能阻断 GABA 的作用。依他唑酯和卡他唑酯，如戊巴比妥，竞争性抑制 α-[3H]二氢印防己毒素的结合，其效力与其对苯二氮卓结合的刺激特性密切相关。这些结果表明，吡唑并吡啶与戊巴比妥一样，通过印防己毒素敏感位点刺激[3H]地西泮结合，该位点不同于γ-氨基丁酸受体位点。依唑酯和苯二氮卓类受体位点之间的这些体外相互作用也可以通过 GABA 拮抗剂荷包牡丹碱进行调节，这与含有三种受体（GABA、苯二氮卓类药物和依唑酯/巴比妥类/印防己毒素）的复合物的存在一致。荷包牡丹碱完全逆转依他唑酯和 GABA 对苯二氮卓结合的影响，但仅部分逆转戊巴比妥的增强作用。戊巴比妥和依唑酯的作用之间的差异，以及上述最大增强作用的差异，表明戊巴比妥可能对某些荷包牡丹碱敏感的苯二氮卓结合位点具有与依唑酯类似的作用，但除此之外，戊巴比妥还可以以既不被依唑酯模仿也不被荷包牡丹碱阻断的方式增强一些其他苯二氮卓结合位点。 （较少的）
The two pyrazolopyridines, etazolate (SQ20009) and cartazolate (SQ65396), enhance the binding of [3H]diazepam to benzodiazepine receptor sites in rat brain. This enhancement is due to a change in affinity without a change in maximal binding. Pentobarbital also enhances [3H]diazepam binding by lowering the K(D). Pentobarbital gives a maximal enhancement of benzodiazepine binding slightly greater than that induced by etazolate, but maximal concentrations of etazolate cannot increase further the maximal enhancement by pentobarbital. By contrast, the enhancement of benzodiazepine binding by γ-aminobutyric acid (GABA) is fully additive with the effect of either etazolate or pentobarbital. The enhancement by γ-aminobutyric acid is blocked specifically by the two γ-aminobutyric acid mimetic compounds, imidazole acetic acid and 4,5,6,7-tetrahydroisoxazolo [5,4-c]pyridine-3-ol (THIP), compounds which do not inhibit the enhancement of diazepam binding by pentobarbital or etazolate. The effects of etazolate and pentobarbital, but not those of GABA, can be blocked competitively by 1 to 10 μM picrotoxinin. Etazolate and cartazolate, like pentobarbital competitively inhibit α-[3H]dihydropicrotoxinin binding with potencies correlating well with their stimulatory properties on benzodiazepine binding. These results suggest that pyrazolopyridines, like pentobarbital, stimulate [3H]diazepam binding through a picrotoxinin-sensitive site which is distinct from the γ-aminobutyric acid receptor site. These in vitro interactions between the etazolate and benzodiazepine receptor sites can be modulated also by the GABA antagonist, bicuculline, consistent with the existence of a complex containing three receptors (GABA, benzodiazepines, and etazolate/barbiturates/picrotoxinin). Bicuculline reverses completely the effects of etazolate and GABA on benzodiazepine binding but reverses only partially the enhancement by pentobarbital. This difference between the effects of pentobarbital and etazolate, as well as differences in their maximal enhancing effects mentioned above, suggests that pentobarbital may have an action similar to etazolate on some bicuculline-sensitive benzodiazepine binding sites, but, in addition, pentobarbital can enhance some other benzodiazepine sites in a manner which is neither mimicked by etazolate nor blocked by bicuculline. (Less)