Pharmacological studies on synthetic flavonoids: comparison with diazepam
Pharmacological studies on synthetic flavonoids: comparison with diazepam
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DOI：
10.1016/s0028-3908(99)00026-x
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发表时间：
1999-07-01
影响因子：
4.7
通讯作者：
Sanger, DJ
中科院分区：
文献类型：
--
作者：
Griebel, G;Perrault, G;Sanger, DJ
本实验比较了两种合成类黄酮（6-溴黄酮和6-溴-3 '-硝基黄酮）与苯二氮卓类（BZ）地西泮的中心BZ-ω结合特征和药理学特征。体外实验表明，虽然地西泮取代了[3 H]氟马西尼与大鼠小脑和脊髓膜中GABA受体的结合，但这两个脑区富含BZ-ω（1）和BZ-ω（2）受体亚型，其最大有效浓度几乎相等一半，6-溴-3 '-硝基黄酮在取代[3 H]氟马西尼与大鼠小脑膜结合（IC（50）=31 nM）方面比脊髓膜（IC（50）=31 nM）更有效。120 nM），表明对BZ-ω（1）受体亚型的选择性。6-溴双黄酮对BZ-ω（1）受体亚型显示出弱亲和力（IC（50）= 970 nM），对B2-ω（2）受体亚型没有亲和力（IC（50）> 1000 nM）。地西泮而不是合成类黄酮增加了由异烟肼产生的阵挛性癫痫发作的潜伏期，从而表明6-溴黄酮和6-溴-3 '-硝基黄酮在体内都没有表现出对GABA受体的可检测的内在活性。两种冲突实验的结果表明，6-溴黄酮（3-10 mg/kg）和6-溴-3 '-硝基黄酮（0.3-1 mg/kg）在惩罚性饮酒实验中引起抗焦虑样活性，而在惩罚性压杆实验中两种药物均无活性。人工合成的黄酮类化合物在惩罚性饮酒过程中所显示的积极作用小于地西泮，并且不被BZ受体拮抗剂氟马西尼所拮抗。在两种探索活动模型中，6-溴黄酮（3-30 mg/kg）和6-溴-3 '-硝基黄酮（0.3-1 mg/kg）在大鼠高架十字迷宫试验中产生抗焦虑样作用，而两种化合物在宽剂量范围内均未能改变小鼠在光/暗试验中的行为。在高架十字迷宫中的作用被氟马西尼拮抗。在小鼠防御测试组合中，小鼠面临自然威胁（大鼠），6-溴黄酮和6-溴-3 '-硝基黄酮在大鼠被引入测试区域后未能降低飞行反应，并且当受试者被限制在直巷中时显示出风险评估行为，并且仅微弱地影响被大鼠追逐的小鼠的风险评估以及在与威胁刺激物强制接触时的防御性咬咬。在药物辨别实验中，6-溴黄酮和6-溴-3 '-硝基黄酮分别高达30和3 mg/kg，不能替代BZ利血平。总之，这些结果未能证明合成的黄酮类化合物6-溴黄酮和6-溴3 ′-硝基黄酮具有类似于或上级于地西泮的抗焦虑样性质，如先前所建议的。此外，他们质疑B2-ω受体对6-溴黄酮和6-溴-3 '-硝基黄酮的行为效应的贡献。(C)1999 Elsevier Science Ltd.保留所有权利。
The present experiments compared the central BZ-omega binding characteristics and pharmacological profiles of two synthetic flavonoids (6-bromoflavone and 6-bromo-3'-nitroflavone) with those of the benzodiazepine (BZ) diazepam. In vitro experiments showed that while diazepam displaced [(3)H]flumazenil binding to the GABA, receptor in membranes from rat cerebellum and spinal cord, two brain areas enriched in the BZ-omega(1) and BZ-omega(2) receptor subtypes, with nearly equivalent half maximally effective concentrations, 6-bromo-3'-nitroflavone was somewhat more potent in displacing [3H]flumazenil binding to membranes from rat cerebellum (IC(50)=31 nM) than from spinal cord (IC(50)=120 nM), indicating selectivity for the BZ-omega(1) receptor subtype. 6-Bromoflavone displayed weak (IC(50) = 970 nM) affinity for the BZ-omega(1) and no affinity for the B2-omega(2) (IC(50) > 1000 nM) receptor subtypes. Diazepam, but not the synthetic flavonoids increased the latency to clonic seizures produced by isoniazid, thereby indicating that neither 6-bromoflavone nor 6-bromo-3'-nitroflavone display detectable intrinsic activity at GABA, receptors in vivo. Results from two conflict tests in rats showed that 6-bromoflavone (3-10 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) elicited anxiolytic-like activity in the punished drinking test, while both drugs were inactive in the punished lever pressing test. The positive effects displayed by the synthetic flavonoids in the punished drinking procedure were smaller than that of diazepam and were not antagonized by the BZ receptor antagonist flumazenil. In two models of exploratory activity, 6-bromoflavone (3-30 mg/kg) and 6-bromo-3'-nitroflavone (0.3-1 mg/kg) produced anxiolytic-like effects in the rat elevated plus-maze test, whereas both compounds failed to modify the behavior of mice in the light/dark test over a wide dose-range. The effects in the elevated plus-maze were antagonized by flumazenil. In the mouse defense test battery, where mice were confronted with a natural threat (a rat), 6-bromoflavone and 6-bromo-3'-nitroflavone failed to decrease flight reactions after the rat was introduced into the test area and risk assessment behavior displayed when subjects were constrained in a straight alley, and only weakly affected risk assessment of mice chased by the rat and defensive biting upon forced contact with the threat stimulus. In a drug discrimination experiment 6-bromoflavone and 6-bromo-3'-nitroflavone up to 30 and 3 mg/kg, respectively, did not substitute for the BZ chlordiazepoxide. Taken together, these results failed to demonstrate that the synthetic flavonoids 6-bromoflavone and 6-bromo3'-nitroflavone possess anxiolytic-like properties similar or superior to that of diazepam, as was suggested previously. Furthermore, they question the contribution of B2-omega receptors to the behavioral effects of 6-bromoflavone and 6-bromo-3'-nitroflavone. (C) 1999 Elsevier Science Ltd. All rights reserved.