X-RAY MAPPING OF OPIATE RECEPTOR SITES

将使用高分辨率x射线绘制阿片受体位置图。 电子密度分布(EDD)和分子的测量 鸦片类药物及相关分子的静电势(MEP)。这些 直到最近，属性还只能从理论上获得 计算。随着实验X射线方法的最新发展， 现在，从相同的实验中不仅可以获得 药物分子，还有EDD和MEP，连同几何结构， 决定药物-受体相互作用的强度。对其他的研究 生物模型化合物表明，这些电子因素现在是 可测量，其精度至少相当于 小分子。 最初，一系列硬性阿片类药物(吗啡、羟吗啡、纳洛啡、 和纳洛酮)将被研究，其范围从有效的激动剂到 纯粹的自行车手。这些研究将被用来确定 受体部位的立体化学和电子要求，以及 试图理解这种微小的结构修改如何导致 在止痛活性上有根本的差异。受体的模型将会 是以原子分辨率构建的，假设它将是 在形状和电子特性上与药物分子互补的。 带电物种和分子碎片将被定位为产生 药物结合和活性之后的相互作用能。一旦 受体位置已被充分描述，将进行研究 具有鸦片类活性的药物逐渐变得更加灵活。此数据 将用来定义结构和结构的相似性 活性药物的电子性质，并进一步表征 受体部位 长期的目标是发展EDD的X射线测量和 MEP成为研究药物受体和药物的通用工具 蛋白质-配体相互作用。

The opiate mu receptor site will be mapped using high-resolution x-ray measurements of the electron density distribution (EDD) and molecular electrostatic potential (MEP) of opiates and related molecules. These properties, until recently, could only be obtained from theoretical calculations. With the recent development of experimental x-ray methods, it is now possible to obtain from the same experiment not only the shape of the drug molecule, but also the EDD and MEP, which along with geometry, dictate the strength of a drug-receptor interaction. Studies of other biological model compounds show that these electronic factors are now measurable with an accuracy at least equivalent to the best calculations on small molecules. Initially, a series of rigid opiates (morphine, oxymorphine, nalorphine, and naloxone) will be studied which span the range from potent agonist to pure antogonist. These studies will be used to identify both the stereochemical and electronic requirements of the receptor site, and to attempt to understand how such small structural modifications may result in radical differences in analgesic activity. A model for the receptor will be constructed at atomic resolution by assuming that it will be complementary both in shape and electronic character to the drug molecule. Charged species and molecular fragments will be positioned to yield interaction energies which follow drug binding and activity. Once the receptor site has been adequately characterized, studies will be made of progressively more flexible drugs with opiate-like activity. This data will be used to define the similarities in both the structural and electronic character of the active drugs, and to further characterize the receptor site The long-term objective is to develop the x-ray measurement of EDD's and MEP's into a tool of general use for the study of drug-receptor and protein-ligand interactions.