Ishizuka H, Sawada Y, Ito K, Sugiyama Y, Suzuki H, Iga T, Hanano M
Faculty of Pharmaceutical Sciences, University of Tokyo, Japan.
J Pharmacol Exp Ther. 1989 Oct;251(1):362-7.
To evaluate the relationship between the pharmacological effect of benzodiazepine (BZP) and BZP receptor (BZP-R) binding in the conscious mouse brain, a response of the local cerebral metabolic rate of glucose utilization (GU) to clonazepam (CNZ) was measured as an index for the pharmacological effect. Two glucose analogs (3-O-[3H]methylglucose and 2-[14C]deoxyglucose) method, originally presented by A. Gjedde was used for determination of GU. In the cerebral cortex, GU decreased to 70 to 80% at 60 min after i.v. administration of CNZ (0.005-1.0 mg/kg), but CNZ did not change the lumped constant, and this effect was diminished completely by the administration of a BZP antagonist, Ro-15-1788 (5 mg/kg). The maximum effect of CNZ on GU (about 30% decrease) was found at 0.1 mg/kg of CNZ, but increasing the dose to 1 mg/kg had very little additional effect. In vivo BZP-R occupancy was measured using [3H]-Ro-15-1788. Receptor occupancy increased from less than 10% at a dose of 0.005 mg/kg up to essentially 100% at doses of 1 mg/kg or greater. ID50 in dose-response curve of the receptor occupancy for CNZ and ED50 in that of decrease in GU were 0.3 and 0.007 mg/kg, respectively . A nonlinear and hyperbolic relationship was observed between the receptor occupancy and the response for the glucose metabolic rate, indicating that BZP exert the maximum glucose metabolic change at a low fractional receptor occupancy (30-40%).
为评估苯二氮䓬（BZP）的药理作用与清醒小鼠脑内BZP受体（BZP-R）结合之间的关系，测量了局部脑葡萄糖代谢率（GU）对氯硝西泮（CNZ）的反应，以此作为药理作用的指标。采用最初由A. 杰德德提出的两种葡萄糖类似物（3-O-[³H]甲基葡萄糖和2-[¹⁴C]脱氧葡萄糖）方法来测定GU。在大脑皮层，静脉注射CNZ（0.005 - 1.0 mg/kg）后60分钟，GU降至70%至80%，但CNZ并未改变集总常数，且给予BZP拮抗剂Ro-15-1788（5 mg/kg）后该效应完全消失。发现CNZ对GU的最大效应（约降低30%）出现在0.1 mg/kg的CNZ剂量时，但将剂量增加至1 mg/kg时，额外效应非常小。使用[³H]-Ro-15-1788测量体内BZP-R占有率。受体占有率从0.005 mg/kg剂量时的不到10%增加至1 mg/kg或更高剂量时的基本100%。CNZ受体占有率剂量反应曲线的半数抑制剂量（ID50）和GU降低曲线的半数有效剂量（ED50）分别为0.3和0.007 mg/kg。在受体占有率与葡萄糖代谢率反应之间观察到非线性双曲线关系，表明BZP在低分数受体占有率（30% - 40%）时发挥最大的葡萄糖代谢变化。
