IDENTIFICATION AND PHARMACODYNAMICS OF LIPOPHILIC LIGAND

一种亲脂性物质，对中心苯二氮卓类药物具有高亲和力 受体已经从大鼠脑组织中提取出来。 亲脂性 一种物质减少γ-氨基丁酸刺激的氯化物摄取 在突触神经体中。 亲脂性物质似乎不是 苯并二氮杂卓、β-咔啉或多肽。 把老鼠关在 单笼饲养一周可能会增加亲脂性 脑组织中的物质。 这项资助的目的应该有助于解释为什么人类在 对“情绪改变”或镇静作用的反应 苯二氮卓类 第一个具体目标是获得亲脂的 纯度为95%至100%。 最先进的光谱 设备被用来确定亲脂的结构 实质内容。 亲脂性物质对中心和 外周苯二氮卓受体的评估是通过其能力， 分别取代3 H-flumazenil和3 H-PK 11195特异性结合。 亲脂性物质对苯二氮卓受体的选择性 是由其取代特异性结合的能力决定的， 对其他受体具有选择性的放射性配体。 的效力 亲脂性化合物在降低蝇蕈醇刺激的氯化物摄取中的作用 突触神经体正在被测量。 的机制 亲脂性物质引发蝇蕈醇刺激的 将澄清氯化物吸收。 氟马西尼，PK 11195和Ro 15 -4513 将检查拮抗蝇蕈醇减少的能力- 亲脂性物质引起的刺激性氯化物摄取。

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. The Lipophilic Substance does not appear to be a benzodiazepine, a beta-carboline or a polypeptide. Housing rats in single cages for a week may increase the presence of the Lipophilic Substance in brain tissue. The objectives of this grant should help explain why humans vary in response to the "mood-altering" or sedating effects of the benzodiazepines. The first specific aim is to obtain the lipophilic substance in 95 to 100 percent purity. State of the art spectroscopic equipment is being used to determine the structure of the lipophilic substance. The affinity of the lipophilic substance for central and peripheral benzodiazepine receptors is being assessed by its ability to displace 3H-flumazenil and 3H-PK11195 specific binding, respectively. The selectivity of the lipophilic substance for benzodiazepine receptors is being determined by its ability to displace the specific binding of radioligands with selectivity for other receptors. The potency of the lipophilic compound in decreasing muscimol-stimulated chloride uptake in synaptoneurosomes is being measured. The mechanism by which the lipophilic substance initiates the decrease in muscimol-stimulated chloride uptake will be clarified. Flumazenil, PK11195 and Ro15-4513 will be examined for an ability to antagonize the reduction in muscimol- stimulated chloride uptake elicited by the lipophilic substance.