Haefely W E
Pharmaceutical Research Department, F. Hoffmann-La Roche & Co., Ltd., Basle, Switzerland.
Int Anesthesiol Clin. 1988 Winter;26(4):262-72. doi: 10.1097/00004311-198802640-00005.
The structure of the GABAA receptor, through which GABA--the main inhibitory neurotransmitter in the mammalian CNS--produces its major synaptic effects, has recently been identified. The GABAA receptor is a member of a family of receptor-operated ion channels to which the nicotinic cholinergic receptor-cation channel and the glycine receptor-anion channel belong. The GABAA receptor, formed by two different subunits with structural homologies, contains at least two pharmacologically important allosteric modulatory sites, one being the BZR. The BZR responds to two classes of active ligands, namely the so-called BZR agonists, which produce a positive modulation of GABAA receptor function resulting in anxiolytic, anticonvulsive, sedative, and muscle relaxant activity, and the so-called BZR inverse agonists, which produce a negative allosteric modulation of the GABAA receptor function resulting in a mirror image of the agonist profile. The effects of these two extreme classes of ligands (with maximal positive and negative intrinsic efficacy, respectively) are blocked by BZR antagonists, ligands of the BZR devoid of relevant intrinsic efficacy. Flumazenil is the first BZR antagonist available for therapeutic use. The molecular basis of the activities of BZR ligands and of their interactions has enormously increased our understanding of the complex function of neuronal receptors and neurotransmitters.
γ-氨基丁酸A型（GABAA）受体的结构最近已被确定，哺乳动物中枢神经系统中的主要抑制性神经递质γ-氨基丁酸（GABA）通过该受体产生其主要的突触效应。GABAA受体是受体操纵离子通道家族的成员，烟碱型胆碱能受体 - 阳离子通道和甘氨酸受体 - 阴离子通道也属于该家族。由具有结构同源性的两种不同亚基形成的GABAA受体含有至少两个药理学上重要的变构调节位点，其中一个是苯二氮䓬受体（BZR）。BZR对两类活性配体有反应，即所谓的BZR激动剂，它们对GABAA受体功能产生正向调节，导致抗焦虑、抗惊厥、镇静和肌肉松弛活性；以及所谓的BZR反向激动剂，它们对GABAA受体功能产生负向变构调节，导致与激动剂作用相反的效应。这两类极端配体（分别具有最大正性和负性内在活性）的作用被BZR拮抗剂阻断，BZR拮抗剂是缺乏相关内在活性的BZR配体。氟马西尼是首个可用于治疗的BZR拮抗剂。BZR配体的活性及其相互作用的分子基础极大地增进了我们对神经元受体和神经递质复杂功能的理解。
