IDENTIFICATION AND PHARMACODYNAMICS OF LIPOPHILIC LIGAND

一种对中枢性苯二氮卓类具有高亲和力的亲脂物质 已经从大鼠的脑组织中提取了受体。亲油性 一种物质可减少γ-氨基丁酸刺激的氯化物摄取 在突触神经体中。这种亲脂物质似乎不是一种 苯二氮、一种β-卡洛林或一种多肽。把老鼠安置在 单笼饲养一周可能会增加亲脂性的存在 脑组织中的物质。 这笔赠款的目标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性 纯度为95%至100%的物质。最先进的光谱学 正在使用设备来确定亲脂性的结构 实质性的。亲脂性物质对中枢神经系统的亲和力 外周苯二氮卓类受体正在通过它的能力进行评估 分别取代3 H-氟马西尼和3 H-PK11195的特异性结合。 亲脂物质对苯二氮卓类受体的选择性 是由它取代特定绑定的能力决定的 对其他受体具有选择性的放射性配基。它的威力在于 亲脂性化合物降低蝇毒酚刺激的大鼠肾小管上皮细胞氯摄取 正在对突触神经体进行测量。这是一种机制 亲脂性物质启动蝇毒酚刺激的减少 氯的吸收将被澄清。氟马西尼、PK11195和Ro15-4513 将接受检查以确定是否有能力对抗蝇草酚的减少- 由亲脂物质引起的刺激氯离子摄取。

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.