Development of Natural Product Based Opioid Receptor Ligands

描述(申请人提供)：尽管经过了半个多世纪的研究，旨在确定新的止痛药，但从吗啡衍生的止痛药仍然是严重疼痛的一线治疗药物。虽然鸦片类药物在临床上的使用很广泛，但它们存在一些严重的缺点。除了几种潜在的副作用外，上瘾的风险总是存在的。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，有必要确定对三种主要阿片受体具有选择性结合的新化合物。这些化合物也将被证明对设计下一代成瘾疗法很有用。据推测，Hasubanan生物碱(HB生物碱)可能满足这一长期需求。不幸的是，需要这些天然产物的非天然对极来充分检验这一假说。因此，必须开发一条有效的合成路线来合成Et-Hb生物碱核心。这一分阶段应用的总体目标是合成和评价具有代表性的Et-Hb生物碱的生物活性。因此，拟议的研究与NIH支持对疾病治疗和治愈至关重要的研究的任务部分相关。通过追求以下三个具体目标，将实现这一国际和平机构的目标。在第一个目标下，将开发一条有效的合成HB生物碱的路线，并通过合成两个具有代表性的家族成员进行演示。这一策略将把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能力。这将通过使用标准的基于细胞的分析来确定受体的选择性和配基功能(激动性或拮抗性)来实现。在第三个目标下，将采用目标1中开发的合成路线，以合成效率和选择性更高的Et-Hb生物碱衍生物。已报道的三种不同阿片受体的X射线晶体结构指导了所提出的类似物的身份。这些类似物旨在加强与结合口袋保守区域的关键残基的相互作用(以提高效力)，并与仅存在于阿片受体中的关键残基建立相互作用(以提高选择性)。这项工作的预期结果将证明Et-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Et-Hb生物碱类似物可以被用作一类新的探针分子，用于识别治疗急性疼痛的新方法。经过适当的修饰，这些相同的探针分子也将被证明对开发新的药物成瘾治疗方法有用。

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.