Wisden W, Yu X, Franks N P
Department Life Sciences, Imperial College London, London, SW7 2AZ, UK.
Handb Exp Pharmacol. 2019;253:279-304. doi: 10.1007/164_2017_56.
Current GABAergic sleep-promoting medications were developed pragmatically, without making use of the immense diversity of GABA receptors. Pharmacogenetic experiments are leading to an understanding of the circuit mechanisms in the hypothalamus by which zolpidem and similar compounds induce sleep at α2βγ2-type GABA receptors. Drugs acting at more selective receptor types, for example, at receptors containing the α2 and/or α3 subunits expressed in hypothalamic and brain stem areas, could in principle be useful as hypnotics/anxiolytics. A highly promising sleep-promoting drug, gaboxadol, which activates αβδ-type receptors failed in clinical trials. Thus, for the time being, drugs such as zolpidem, which work as positive allosteric modulators at GABA receptors, continue to be some of the most effective compounds to treat primary insomnia.
当前的GABA能促眠药物是根据实际需要研发的，并未利用GABA受体的巨大多样性。药物遗传学实验正在促使人们了解下丘脑的回路机制，通过该机制唑吡坦及类似化合物在α2βγ2型GABA受体上诱导睡眠。作用于更具选择性受体类型的药物，例如作用于在下丘脑和脑干区域表达的含有α2和/或α3亚基的受体的药物，原则上可用作催眠药/抗焦虑药。一种极具前景的促眠药物加波沙朵，可激活αβδ型受体，但在临床试验中失败了。因此，目前，像唑吡坦这类在GABA受体上作为正性变构调节剂起作用的药物，仍然是治疗原发性失眠最有效的一些化合物。
