IDENTIFICATION AND PHARMACODYNAMICS OF LIPOPHILIC LIGAND

亲脂性配体的鉴定和药效学

• 批准号: 3440918
• 负责人: HAROLD L KOMISKEY
• 金额: $ 8.58万
• 依托单位: XAVIER UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-05-01 至 1992-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3440918
• 关键词: benzodiazepine receptor; chemical stimulation; drug metabolism; gamma aminobutyrate; hydropathy; laboratory rat; pharmacology

A lipophilic substance with high affinity for central benzodiazepine receptors has been extracted from rat brain tissue. The lipophilic substance reduces gamma-aminobutyric acid-stimulated uptake of chloride in synaptoneurosomes. In preliminary studies the benzodiazepine antagonist, flumazepil, blocked the inhibitory effect of the lipophilic substance on gamma-aminobutyric acid- stimulated chloride uptake. The lipophilic substance does not appear to be a benzodiazepine, a beta-carboline or a polypeptide. The objectives of this grant should help explain why humans vary in response to the benzodiazepines. The first specific aim is to obtain the lipophilic substance in 95 to 100 purity. State of the art spectroscopic equipment will be used to determine the structure of the lipophilic substance. The affinity of the lipophilic substance for central and peripheral benzodiazepine receptors will be assessed by its ability to displace -H-flumazepil and -H-PK11195 specific binding, respectively. The selectivity of the lipophilic substance for benzodiazepine receptors will be determined by its ability to displace the specific binding of radio-ligands with selectivity for other receptors. The potency of the lipophilic compound in decreasing muscimol-stimulated chloride uptake in synaptoneurosomes will be measured. To control for stress induced alterations of chloride transport, a handled-habituated group will be included in these latter studies. The mechanism by which the lipophilic substance initiates the decrease in muscimol-stimulated chloride uptake will be clarified. Flumazepil, PK11195 and Ro15- 4513 will be examined for an ability to antagonize the reduction in muscimol-stimulated chloride uptake elicited by the lipophilic substance.

对中枢具有高亲和力的亲脂性物质 苯二氮卓受体已从大鼠脑组织中提取。 亲脂性物质减少γ-氨基丁酸刺激 突触神经体中氯化物的摄取。 初步研究中 苯二氮卓类拮抗剂氟马西平可阻断抑制作用 亲脂性物质对γ-氨基丁酸的影响- 刺激氯离子的吸收。 亲脂性物质不 似乎是苯二氮卓类、β-咔啉或多肽。 这笔赠款的目标应该有助于解释为什么人类存在差异 对苯二氮卓类药物的反应。 第一个具体目标是 获得纯度为95至100的亲脂性物质。 的状态 将使用艺术光谱设备来确定结构 的亲脂性物质。 亲脂性的亲和力 中枢和外周苯二氮卓受体的物质 通过其取代-H-氟马西平和-H-PK11195的能力进行评估 分别具有特异性结合。 亲脂性的选择性 苯二氮卓受体的物质将由其决定 取代放射性配体的特异性结合的能力 对其他受体的选择性。 亲脂性的效力 化合物可减少蝇蕈醇刺激的氯化物吸收 将测量突触神经体。 控制压力引起的 氯化物运输的改变，习惯于处理的群体将 包括在后面的这些研究中。 该机制通过 亲脂性物质引发蝇蕈醇刺激的减少 氯离子的吸收将得到澄清。 氟马西匹尔、PK11195 和 Ro15- 第4513章 将被检查对抗还原的能力 在由亲脂性物质引起的蝇蕈醇刺激的氯吸收中 物质。