PDF(Pubmed)
Abstract：
Methaqualone, a quinazolinone marketed commercially as Quaalude, is a central nervous system depressant that was used clinically as a sedative-hypnotic, then became a notorious recreational drug in the 1960s-80s. Due to its high abuse potential, medical use of methaqualone was eventually prohibited, yet it persists as a globally abused substance. Methaqualone principally targets GABAA receptors, which are the major inhibitory neurotransmitter-gated ion channels in the brain. The restricted status and limited accessibility of methaqualone have contributed to its pharmacology being understudied. Here, we use cryo-EM to localize the GABAA receptor binding sites of methaqualone and its more potent derivative, PPTQ, to the same intersubunit transmembrane sites targeted by the general anesthetics propofol and etomidate. Both methaqualone and PPTQ insert more deeply into subunit interfaces than the previously-characterized modulators. Binding of quinazolinones to this site results in widening of the extracellular half of the ion-conducting pore, following a trend among positive allosteric modulators in destabilizing the hydrophobic activation gate in the pore as a mechanism for receptor potentiation. These insights shed light on the underexplored pharmacology of quinazolinones and further elucidate the molecular mechanisms of allosteric GABAA receptor modulation through transmembrane binding sites.
摘要：
甲喹酮,喹唑啉酮作为Quaalude在商业上销售，是一种中枢神经系统抑制剂，临床上用作镇静催眠药，然后在20世纪60-80年代成为臭名昭著的娱乐性药物。由于其高滥用潜力，甲喹酮的医疗用途最终被禁止，然而，它仍然是一种全球滥用的药物。甲喹酮主要靶向GABAA受体，它们是大脑中主要的抑制性神经递质门控离子通道。甲喹酮的限制状态和有限的可及性导致其药理学研究不足。这里,我们使用cryo-EM定位甲喹酮及其更有效的衍生物的GABAA受体结合位点，PPTQ,全身麻醉药丙泊酚和依托咪酯靶向的相同亚基间跨膜位点。甲喹酮和PPTQ都比先前表征的调节剂更深入地插入亚基界面。喹唑啉酮与该位点的结合导致离子传导孔的细胞外半部变宽，遵循正变构调节剂之间的趋势，使孔中的疏水激活门不稳定，这是受体增强的机制。这些见解揭示了喹唑啉酮的未充分开发的药理学，并进一步阐明了通过跨膜结合位点调节变构GABAA受体的分子机制。
