Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation
Benzodiazepine modulation of partial agonist efficacy and spontaneously active GABAA receptors supports an allosteric model of modulation
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DOI：
10.1038/sj.bjp.0706251
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发表时间：
2005-08-01
影响因子：
7.3
通讯作者：
Gibbs, TT
中科院分区：
文献类型：
--
作者：
Downing, SS;Lee, YT;Gibbs, TT
1苯二氮类药物(BZD)因其治疗指数高、毒性低而被广泛应用40多年。虽然BZD被认为主要作为GABA受体的变构调节剂，但其调节机制还不是很清楚。2研究了具有两个结合伽马氨基丁酸(GABA)和一个结合BZD样调节剂的变构模型的适用性。3该模型预测BZDS应该增强部分激动剂的疗效。4与这一预测一致，地西潘提高了GABA(A)受体部分激动剂Kojic amine在鸡脊髓神经元中的疗效。5为了进一步测试该模型的有效性，地西潘、氟西潘、6与变构模型的预测一致，所有三种调节剂都作为自发活性受体的直接激动剂。7结果表明，BZD样调节剂通过将开放通道活动状态相对于非活动状态稳定不到1千卡，从而增强GABA反应的幅度，这类似于单个氢键提供的稳定能量。
1 Benzodiazepines (BZDs) have been used extensively for more than 40 years because of their high therapeutic index and low toxicity. Although BZDs are understood to act primarily as allosteric modulators of GABA, receptors, the mechanism of modulation is not well understood.2 The applicability of an allosteric model with two binding sites for gamma-aminobutyric acid (GABA) and one for a BZD-like modulator was investigated.3 This model predicts that BZDs should enhance the efficacy of partial agonists.4 Consistent with this prediction, diazepam increased the efficacy of the GABA(A) receptor partial agonist kojic amine in chick spinal cord neurons.5 To further test the validity of the model, the effects of diazepam, flurazepam, and zolpidem were examined using wild-type and spontaneously active mutant alpha 1(L263S)beta 3 gamma 2 GABA(A) receptors expressed in HEK-293 cells.6 In agreement with the predictions of the allosteric model, all three modulators acted as direct agonists for the spontaneously active receptors.7 The results indicate that BZD-like modulators enhance the amplitude of the GABA response by stabilizing the open channel active state relative to the inactive state by less than 1 kcal, which is similar to the energy of stabilization conferred by a single hydrogen bond.