Development of Natural Product Based Opioid Receptor Ligands

基于天然产物的阿片受体配体的开发

基本信息

批准号：
8582228
负责人：
Andrew Michael Harned
金额：
$ 18.09万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-01 至 2017-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Despite well over half a century of research aimed at identifying new analgesics, analgesics derived from morphine continue to serve as the front-line treatment for severe pain. While the clinical use of opiates is widespread, they suffer from a number of serious drawbacks. In addition to several potential side effects, the risk of addiction will always be present. This risk is further exacerbated by tolerance that develops with many patients. In order to overcome these problems, there is a need to identify new compounds that have selective binding toward the three main opioid receptors. Such compounds will also prove useful for designing the next- generation of addiction therapeutics. It has been hypothesized that the hasubanan alkaloids (HB alkaloids) may meet this long-standing need. Unfortunately, the unnatural antipode of these natural products is needed to adequately test this hypothesis. Consequently, an efficient synthetic route to the ent-HB alkaloid core must be developed. The overall objectives of this phased application is to synthesize and evaluate the bioactivity of representative ent-HB alkaloids. Thus, the proposed research is relevant to that part of the NIH's mission that supports research that is fundamental to disease treatment and cure. This PI's objectives will be met by pursuing the following three specific aims. Under the first aim, an efficient synthetic route to the HB alkaloids will be developed and demonstrated by synthesizing two representative family members. This strategy will integrate the formation of the C12-C13 and C14-N bonds with the formation of the B and D rings. Under the second aim, the compounds synthesized in Aim 1 will be evaluated for their ability to function as opioid receptor ligands. This will be accomplished by using standard cell-based assays to determine receptor selectivity and ligand function (agonism or antagonism). Under the third aim, the synthetic route developed in Aim 1 will be adapted in order to synthesis ent-HB alkaloid derivatives with increased potency and selectivity. The identity of the proposed analogs has been guided by the reported X-ray crystal structures of the three different opioid receptors. These analogs have been designed to strengthen interactions with key residues in the conserved region of the binding pocket (to increase potency) and to establish an interaction with a key residue found only in the opioid receptor (to increase selectivity). The expected outcome of this work will be a demonstration that the ent-HB alkaloids do indeed have potent affinity toward the opioid receptors. This will have a positive impact on human health because ent-HB alkaloid analogs can then be used as a new class of probe molecules for identifying new treatments for acute pain. With the proper modifications, these same probe molecules will also prove useful for the development of new treatments for drug addiction.

描述（由申请人提供）：尽管半个多世纪的研究旨在确定新的镇痛药，吗啡衍生的镇痛药仍然是严重疼痛的一线治疗方法。虽然阿片剂的临床使用很广泛，但它们存在许多严重的缺点。除了一些潜在的副作用之外，成瘾的风险始终存在。许多患者产生的耐受性进一步加剧了这种风险。为了克服这些问题，需要鉴定对三种主要阿片受体具有选择性结合的新化合物。此类化合物还将被证明可用于设计下一代成瘾疗法。据推测，哈苏巴南生物碱（HB 生物碱）可以满足这一长期存在的需求。不幸的是，需要这些天然产物的非天然对映体来充分检验这一假设。因此，必须开发 ent-HB 生物碱核心的有效合成路线。本阶段应用的总体目标是合成和评估代表性 ent-HB 生物碱的生物活性。因此，拟议的研究与 NIH 使命的一部分相关，即支持对疾病治疗和治愈至关重要的研究。该 PI 的目标将通过追求以下三个具体目标来实现。第一个目标是通过合成两个具有代表性的家族成员来开发和论证 HB 生物碱的有效合成路线。该策略将 C12-C13 和 C14-N 键的形成与 B 环和 D 环的形成结合起来。在第二个目标下，将评估目标 1 中合成的化合物作为阿片受体配体的功能。这将通过使用标准的基于细胞的测定来确定受体选择性和配体功能（激动或拮抗）来完成。在第三个目标下，将调整目标 1 中开发的合成路线，以合成具有更高效力和选择性的 ent-HB 生物碱衍生物。所提出的类似物的身份是根据已报道的三种不同阿片受体的 X 射线晶体结构来确定的。这些类似物旨在加强与结合袋保守区域中关键残基的相互作用（以增加效力），并与仅在阿片受体中发现的关键残基建立相互作用（以增加选择性）。这项工作的预期结果将证明 ent-HB 生物碱确实对阿片受体具有强大的亲和力。这将对人类健康产生积极影响，因为 ent-HB 生物碱类似物可以用作一类新型探针分子，用于识别急性疼痛的新疗法。通过适当的修饰，这些相同的探针分子也将被证明可用于开发药物成瘾的新疗法。