Meldrum B S, Chapman A G
Epilepsia. 1986;27 Suppl 1:S3-13. doi: 10.1111/j.1528-1157.1986.tb05731.x.
Benzodiazepines (BDZ) interact with components of neuronal membranes to modify excitability in three different ways. Action at a high affinity central receptor (dissociation constant, KD, of 3 nM) linked to the GABAA recognition site enhances the inhibitory action of GABA by increasing the number of openings of Cl- channels produced by a given concentration of GABA. This effect correlates with anticonvulsant activity as evaluated in the antipentylenetetrazol test in animals and with antimyoclonic activity in human beings. It also correlates with anxiolytic activity. Action at a lower affinity membrane site (KD 100 nM to 1 microM) limits repetitive firing as observed in isolated neurons (in a manner similar to the action of phenytoin or carbamazepine). This does not depend primarily on neurotransmitter mechanisms, but probably involves an increase in the population of sodium channels in the inactive state. Action at a lower affinity site (KD 45 microM) in presynaptic terminals decreases voltage sensitive Ca++ conductance and, by limiting Ca++ entry, decreases neurotransmitter release. The two lower affinity BDZ systems may be responsible for therapeutic action in status epilepticus and for sedative side-effects. The high affinity central benzodiazepine binding sites can be differentiated into BZ1 and BZ2 receptors by ligands (such as triazolopyridazines and Quazepam) that preferentially act on BZ1 sites. There are regional differences in the density of the two receptor subtypes, but these have not yet been correlated with specific actions of benzodiazepines. Differences between various 1,4- and 1,5-benzodiazepines in terms of therapeutic action in epilepsy and neurologic side-effects can probably be explained on the basis of variation in full or partial agonist action at the high affinity central receptor, or differing relative action at the high and low affinity receptors.
苯二氮䓬类药物（BDZ）与神经元膜成分相互作用，通过三种不同方式改变兴奋性。作用于与GABAA识别位点相连的高亲和力中枢受体（解离常数KD为3 nM），通过增加给定浓度GABA产生的Cl-通道开放数量，增强GABA的抑制作用。这种效应与动物戊四氮试验中评估的抗惊厥活性以及人类的抗肌阵挛活性相关。它还与抗焦虑活性相关。作用于较低亲和力的膜位点（KD为100 nM至1 μM）可限制分离神经元中观察到的重复放电（类似于苯妥英或卡马西平的作用方式）。这主要不依赖于神经递质机制，可能涉及非活性状态下钠通道数量的增加。作用于突触前终末较低亲和力位点（KD为45 μM）可降低电压敏感性Ca++电导，并通过限制Ca++内流减少神经递质释放。两个较低亲和力的BDZ系统可能负责癫痫持续状态的治疗作用和镇静副作用。高亲和力中枢苯二氮䓬结合位点可通过优先作用于BZ1位点的配体（如三唑并哒嗪类和夸西泮）分为BZ1和BZ2受体。两种受体亚型的密度存在区域差异，但尚未与苯二氮䓬类药物的特定作用相关联。各种1,4 - 和1,5 - 苯二氮䓬类药物在癫痫治疗作用和神经副作用方面的差异，可能基于其在高亲和力中枢受体上完全或部分激动剂作用的变化，或在高亲和力和低亲和力受体上不同的相对作用来解释。
