化学
苯二氮卓
药理学
受体
药效学
体内
劳拉西泮
内科学
γ-氨基丁酸受体
内分泌学
放射性配体
药代动力学
麻醉
生物化学
生物
医学
生物技术
作者
Lawrence G. Miller,David J. Greenblatt,Steven M. Paul,Richard I. Shader
出处
期刊:PubMed
日期:1987-02-01
卷期号:240 (2): 516-22
被引量:28
摘要
A tracer radioligand technique employing [3H]Ro 15-1788 was used to measure in vivo benzodiazepine receptor occupancy in mice. Animals were administered clonazepam (CNZ) or lorazepam (LRZ) i.p. or i.v., followed by [3H]Ro 15-1788. Plasma and cerebral cortical concentrations of the drug and cortical benzodiazepine receptor occupancy were determined at varying doses and times after administration. For both drugs, plasma and brain concentrations decreased in parallel with decreasing doses and with time, and the brain/plasma ratios remained constant. Receptor occupancy was maximal for CNZ and LRZ at doses above 1 and 4 mg/kg, respectively, and decreased with decreasing doses. Comparison of receptor occupancy with brain concentration yielded IC50 values of 21 ng/g for CNZ and 133 ng/g for LRZ. The apparent dissociation constant (Kd) for CNZ was 56 pmol/g and, for LRZ, 372 pmol/g. Hill plots yielded slopes of 1.30 for CNZ and 1.71 for LRZ. Alterations in the nonspecific uptake or elimination of Ro 15-1788 did not explain occupancy changes, inasmuch as brain concentrations of unlabeled Ro 15-1788 (6 mg/kg) were not changed by LRZ administration. The correlation between receptor occupancy and the pharmacodynamic actions of these drugs in blocking pentylenetetrazol seizures and inducing rotarod ataxia indicated that ED50 for these effects occurred at receptor occupancy of 30 to 60% for both drugs.
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