X-RAY MAPPING OF OPIATE RECEPTOR SITES

阿片μ受体位点将使用高分辨率x射线 电子密度分布（EDD）和分子 阿片类药物和相关分子的静电势（MEP）。 这些 性能，直到最近，只能从理论上获得 计算。 随着实验X射线方法的最新发展， 现在可以从相同的实验中不仅获得 药物分子，还有EDD和MEP，它们沿着几何形状， 决定了药物-受体相互作用的强度。 其他研究 生物模型化合物表明，这些电子因素现在 可测量的准确度至少相当于最好的计算 小分子。 最初，一系列刚性阿片类药物（吗啡，羟吗啡，纳洛啡， 和纳洛酮）将被研究，其范围从强效激动剂到 纯粹的自我控制者 这些研究将用于确定 受体位点的立体化学和电子要求，以及 试图了解这种小的结构变化如何导致 镇痛活性的根本差异。 该受体的模型将 以原子分辨率构造，假设它将 在形状和电子特性上与药物分子互补。 带电物质和分子碎片将被定位以产生 药物结合和活性后的相互作用能。 一旦 受体位点已充分表征，将研究 具有阿片样活性的逐渐更灵活的药物。 该数据 将用于定义结构和 活性药物的电子特性，并进一步表征 受体位点 长期目标是开发EDD的X射线测量，并 MEP已成为研究药物-受体的通用工具， 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.