SELECTIVE NONPEPTIDE OPIOID LIGANDS

描述：（申请人摘要） 该项目的长期目标是发展有选择的 非肽配体作为研究阿片受体家族的工具， 密切相关的同源受体。 这些配体将用于 药理学研究，以调查受体类型的作用， 亚型，并作为可能导致发现新受体的工具， 阿片受体家族 此外，配体将用于探测 不同阿片受体识别位点的分子结构 通过结合分子建模和结合研究， 野生型和突变型受体。 配体的潜在临床应用 在这个实验室开发的将在合作的基础上进行， 药物滥用、镇痛和HIV-1领域。 本申请的具体目标包括以下项目：a） 含芳香环的吗啡喃类化合物的合成及生物活性研究 基团被限制在一个特定的构象， 努力开发δ亚型选择性拮抗剂; B）合成 构象受限的脒主要来源于纳洛酮，在一个 努力获得亚型选择性κ拮抗剂。 这些成员 该系列还将在克隆的野生型和突变型κ受体上进行测试， 以获得关于拮抗剂识别位点的信息; c） kappa激动剂的合成和评价， 外周给药时进入CNS的能力。 议员 系列作为研究外周血淋巴细胞的药理学工具， 不涉及中枢κ受体的κ受体; κ受体亲和标记物的设计和合成 与已知的κ拮抗剂相关。 这些配体具有潜在的用途， 药理学工具和作为探针以鉴定拮抗剂上的残基 识别位点的选择性拮抗剂的开发; 淋巴细胞衍生的阿片受体，似乎是δ亚型。 这 将涉及筛选从PI中选择的化合物。的图书馆 阿片样物质配体以获得先导化合物。 建模研究将 根据神经元和神经元之间的差异进行 淋巴细胞衍生的受体，以获得有关 f）ORL 1选择性非肽的开发 从P.I.的阿片配体库。

DESCRIPTION: (Applicant's Abstract) The long-term objectives of this project are the development of selective nonpeptide ligands as tools to investigate the opioid receptor family and closely related homologous receptors. These ligands will be used in pharmacological studies to investigate the roles of receptor types and subtypes, and as tools that may lead to the discovery of new receptors in the opioid receptor family. Also, the ligands will be employed to probe the molecular architecture of different opioid receptor recognition sites through a combination of molecular modeling and binding studies to cloned wild-type and mutant receptors. Potential clinical applications of ligands developed in this laboratory will be pursued on a collaborative basis in the areas of substance abuse, analgesia and HIV-1. The specific aims of this application include the following projects: a) Synthesis and biological evaluation of morphinans that contain aromatic groups that are restricted to a variety of specific conformations in an effort to develop delta subtype-selective antagonists; b) Synthesis of conformationally constrained amidines derived mainly from naltrexone, in an effort to obtain subtype-selective kappa antagonists. Members of these series also will be tested on cloned wild-type and mutant kappa receptors in order to obtain information on the antagonist recognition site; c) The synthesis and evaluation of kappa agonists that have greatly restricted capacity to enter the CNS when administered peripherally. Members of this series are of interest as pharmacologic tools to investigate peripheral kappa receptors without involvement of central kappa receptors; d) The design and synthesis of kappa receptor affinity labels that are structurally related to known kappa antagonists. These ligands have potential uses as pharmacologic tools and as probes to identify residues at the antagonist recognition site; e) The development of selective antagonists for the lymphocyte-derived opioid receptor that appears to be a delta subtype. This will involve the screening of selected compounds from the P.I.'s library of opioid ligands in an effort to obtain lead compounds. Modeling studies will be conducted based on differences between the neuronal and lymphocyte-derived receptors in an effort to obtain information on the recognition sites; and f) The development of ORLl-selective nonpeptide ligands from leads obtained from the P.I.'s library of opioid ligands.