IDENTIFICATION AND PHARMACODYNAMICS OF LIPOPHILIC LIGAND

一种亲脂性物质，对中枢神经系统具有高亲和力， 已从大鼠脑组织中提取了苯二氮受体。 亲脂性物质减少γ-氨基丁酸刺激的 突触神经体中氯的摄取。 在初步研究中 苯二氮卓类拮抗剂氟马扎匹可阻断抑制性 亲脂性物质对γ-氨基丁酸的影响- 刺激氯化物摄取。 亲脂性物质不 似乎是苯二氮卓类、β-咔啉或多肽。 这项拨款的目的应该有助于解释为什么人类会有不同的 对苯二氮卓类药物的反应 第一个具体目标是 得到纯度为95 ~ 100的亲脂性物质。 状态 艺术光谱设备将用于确定结构 亲脂性物质。 亲脂性 用于中枢和外周苯二氮卓受体的物质将 通过其置换-H-氟马扎匹和-H-PK 11195的能力进行评估 具体的结合。 亲脂性的选择性 苯二氮卓受体的物质将通过其 能够取代放射性配体与 对其他受体的选择性。 亲脂剂的效力 化合物在降低蝇蕈醇刺激的氯化物摄取中的作用 将测量突触神经体。 为了控制压力引起的 氯离子转运的改变，一个处理习惯的群体将 将被纳入这些研究中。 的机制 亲脂性物质引发蝇蕈醇刺激的 将澄清氯化物吸收。 氟马扎匹、PK 11195和Ro 15- 4513将被检查对抗减少的能力 在亲脂性β-内酰胺酶诱导的蝇蕈醇刺激的氯化物摄取中 实质内容。

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.