X-RAY MAPPING OF OPIATE RECEPTOR SITES

阿片类药物Mu受体位置将使用精确的高分辨率 低温下的分辨率x射线测量 电子密度分布与分子静电 一系列阿片类药物及相关分子的电势。因为x- 射线被分子中的电子散射，这是可能的 TO单晶的精确X射线衍射法测量 获得一个实验性的电子三维图谱 分发。由于x射线也提供了详细的描述 分子的形状，无论是立体化学的还是 决定药物受体强度的电子因素 相互作用可以从相同的实验中获得。 鸦片类药物是研究最多的药物之一 实验方法和理论方法，并保持了 作为强效镇痛剂和AS的广泛医疗用途 药物过量治疗中的拮抗剂。现代的方法 分子药物设计有望发现许多新的 如果药物-受体相互作用的细节是 明白了。然而，阿片受体并没有 具有结构特征的。该项目的方法将 是利用结构和实验电子分布 测量了一系列鸦片类药物建立的三维 通过假设它在两个方面是互补的 活性药物分子的形状和电荷分布。特定的 待研究的药物分子包括刚性阿片类药物，如 纳洛啡、可待因、氢吗啡酮和更灵活的药物 与阿片类活性如芬太尼和度冷丁添加 到一个包含实验电子分布的数据库 纳洛酮、吗啡和美沙酮。 我们的长期目标是发展x射线测量 电子密度分布与分子静电 有潜力成为药物研究的通用工具-- 受体相互作用。

The opiate mu receptor site will be mapped using accurate high- resolution x-ray measurements at low temperature of the electron density distributions and molecular electrostatic potentials of a series of opiates and related molecules. Since x- rays are scattered by electrons in a molecule it is possible using accurate x-ray diffraction measurements of single-crystals to obtain an experimental three-dimensional map of the electron distribution. And since x-rays also provide a detailed description of the shape of a molecule, both the stereochemical and electronic factors which determine the strength of drug-receptor interactions may be obtained from the same experiments. Drugs of the opiate class are among the most highly studied by both experimental and theoretical methods, and remain of widespread medical use both as potent analgesics and as antagonists in the treatment of overdoses. Modern methods of molecular drug design offer the promise of discovering many new drugs if the details of the drug-receptor interaction are understood. The opiate receptor, however, has not been structurally characterized. The methodology of this project will be to use the structures and experimental electron distributions measured on a series of opiate drugs to build a three-dimensional model of the receptor by assuming it is complementary both in shape and charge distribution to active drug molecules. Specific drug molecules to be studied include rigid opiates such as nalorphine, codeine, and hydromorphone and more flexible drugs with opiate-like activity such as fentanyl and meperidine to add to a data base which includes experimental electron distributions of naloxone, morphine, and methadone. The long-term objective is to develop the x-ray measurement of electron density distributions and molecular electrostatic potentials into a tool of general utility for the study of drug- receptor interactions.