Downing Scott S, Lee Yan T, Farb David H, Gibbs Terrell T
Laboratory of Molecular Neurobiology, Department of Pharmacology, Boston University School of Medicine, 715 Albany St, Boston, MA 02118, USA.
Br J Pharmacol. 2005 Aug;145(7):894-906. doi: 10.1038/sj.bjp.0706251.
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(A) receptors, the mechanism of modulation is not well understood. The applicability of an allosteric model with two binding sites for gamma-aminobutyric acid (GABA) and one for a BZD-like modulator was investigated. This model predicts that BZDs should enhance the efficacy of partial agonists. Consistent with this prediction, diazepam increased the efficacy of the GABA(A) receptor partial agonist kojic amine in chick spinal cord neurons. To further test the validity of the model, the effects of diazepam, flurazepam, and zolpidem were examined using wild-type and spontaneously active mutant alpha1(L263S)beta3gamma2 GABA(A) receptors expressed in HEK-293 cells. In agreement with the predictions of the allosteric model, all three modulators acted as direct agonists for the spontaneously active receptors. 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.
苯二氮䓬类药物（BZDs）因其高治疗指数和低毒性已被广泛使用40多年。尽管人们认为BZDs主要作为γ-氨基丁酸（GABA）A受体的变构调节剂起作用，但其调节机制尚不清楚。研究了一种具有两个GABA结合位点和一个BZD样调节剂结合位点的变构模型的适用性。该模型预测BZDs应增强部分激动剂的效力。与这一预测一致，地西泮增加了GABA A受体部分激动剂曲酸胺在鸡脊髓神经元中的效力。为了进一步测试该模型的有效性，使用在HEK-293细胞中表达的野生型和自发活性突变体α1（L263S）β3γ2 GABA A受体研究了地西泮、氟西泮和唑吡坦的作用。与变构模型的预测一致，所有三种调节剂对自发活性受体均表现为直接激动剂。结果表明，BZD样调节剂通过使开放通道活性状态相对于非活性状态稳定不到1千卡来增强GABA反应的幅度，这与单个氢键赋予的稳定能量相似。
