Chan C Y, Farb D H
J Neurosci. 1985 Sep;5(9):2365-73. doi: 10.1523/JNEUROSCI.05-09-02365.1985.
The ability of several homologous benzodiazepine and heterologous nonbenzodiazepine ligands to alter the conductance increase induced in spinal cord neurons by gamma-aminobutyric acid (GABA) was determined. Complete dose-response curves were carried out on individual neurons, reducing error introduced by cell-to-cell variability. The efficacies of modulation differ for "classical" benzodiazepines and novel nonbenzodiazepine drugs in a manner consistent with a model of control of GABA receptor action through a common receptor. There was no apparent correlation between efficacy and potency. CL 218,872, a triazolopyridazine, gave the lowest efficacy of the tranquilizers tested. Ro 15-1788 (an imidazobenzodiazepine) potentiated g GABA with high potency and low efficacy, consistent with an action as a partial agonist and an "antagonist" of classical benzodiazepine action. In order of increasing efficacy, Ro 15-1788, CL 218,872, and flurazepam are partial agonists, whereas clonazepam, chlordiazepoxide, diazepam, and flunitrazepam are full agonists. The beta-carboline drugs methyl-beta-carboline-3-carboxylate (beta-CCM) and methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM) are "anxiogenics" and convulsants that were found to exert through the benzodiazepine receptor-inhibitory and apparently insurmountable control of g GABA . beta-CCM and DMCM display large negative efficacies and act like effectors at a site distinct from the picrotoxin-sensitive chloride ionophore and coincident with the benzodiazepine site. The actions of these different benzodiazepine receptor ligands in vivo range from anxiolytic and anticonvulsant to anxiogenic and convulsant. Efficacy rather than potency almost certainly determines the qualitative nature of the pharmacological actions of these drugs.
测定了几种同源苯二氮䓬类和异源非苯二氮䓬类配体改变γ-氨基丁酸（GABA）诱导的脊髓神经元电导增加的能力。对单个神经元进行了完整的剂量-反应曲线测定，减少了细胞间变异性引入的误差。“经典”苯二氮䓬类药物和新型非苯二氮䓬类药物的调节效能不同，其方式与通过共同受体控制GABA受体作用的模型一致。效能和效价之间没有明显的相关性。三唑并哒嗪类药物CL 218,872在所测试的镇静剂中效能最低。Ro 15-1788（一种咪唑并苯二氮䓬）高效能、低效能地增强GABA电导，这与其作为部分激动剂和经典苯二氮䓬作用的“拮抗剂”的作用一致。按效能增加的顺序，Ro 15-1788、CL 218,872和氟西泮是部分激动剂，而氯硝西泮、氯氮䓬、地西泮和氟硝西泮是完全激动剂。β-咔啉类药物甲基-β-咔啉-3-羧酸酯（β-CCM）和甲基-6,7-二甲氧基-4-乙基-β-咔啉-3-羧酸酯（DMCM）是“致焦虑剂”和惊厥剂，发现它们通过苯二氮䓬受体对GABA电导发挥抑制作用且显然是不可克服的。β-CCM和DMCM显示出较大的负效能，并且在与苦味毒素敏感的氯离子载体不同且与苯二氮䓬位点重合的位点上起效应器的作用。这些不同的苯二氮䓬受体配体在体内的作用范围从抗焦虑和抗惊厥到致焦虑和惊厥。几乎可以肯定，效能而非效价决定了这些药物药理作用的定性性质。
