Development of Natural Product Based Opioid Receptor Ligands

基于天然产物的阿片受体配体的开发

• 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
• 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
• 来源: https://reporter.nih.gov/project-details/8582228
• 关键词: Acids; Acute Pain; Adverse effects; Affinity; Agonist; Alkaloids; Analgesics; Binding; Binding Sites; Biological; Biological Assay; Biological Factors; Cells; Chemicals; Chemistry; Clinical; Codeine; Development; Disease; Drug Addiction; Evaluation; Family member; Foundations; Goals; Health; High Pressure Liquid Chromatography; Human; Lead; Ligands; Medicine; Mission; Modification; Morphinans; Morphine; Opiates; Opioid Receptor; Opioid Receptor Binding; Outcome; Oxidants; Pain; Patients; Phase; Positioning Attribute; Reporting; Research; Research Support; Resolution; Risk; Roentgen Rays; Route; Source; Structure; Substance abuse problem; Testing; Therapeutic; Work; addiction; alkyl group; analog; base; cyclohexadienone; design; experience; meetings; next generation; novel; opiate alkaloid; public health relevance; receptor; small molecule

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）：尽管有半个多世纪的研究旨在识别新的镇痛药，但源自吗啡的镇痛药仍然是严重疼痛的前线治疗方法。虽然鸦片的临床使用是普遍的，但它们遭受了许多严重的缺点。除了几种潜在的副作用外，成瘾的风险始终存在。与许多患者发展的耐受性进一步加剧了这种风险。为了克服这些问题，有必要识别与三个主要阿片类药物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治疗剂。已经假设Hasubanan生物碱（HB生物碱）可能满足这种长期的需求。不幸的是，需要这些天然产物的不自然抗模具来充分检验这一假设。因此，必须开发有效的通往ENT-HB生物碱核心的合成途径。该分阶段应用的总体目标是合成和评估代表性HB生物碱的生物活性。因此，拟议的研究与支持疾病治疗和治愈基础的研究的NIH任务的那部分有关。通过追求以下三个特定目标，将实现此PI的目标。在第一个目标下，将通过合成两个代表性家庭成员来开发和证明有效的HB生物碱途径。该策略将与B和D环的形成结合C12-C13和C14-N键的形成。在第二个目标下，将评估AIM 1中合成的化合物作为其作为阿片受体配体的功能。这将通过使用基于标准细胞的测定来确定受体选择性和配体功能（激动剂或拮抗作用）来实现。在第三个目标下，将在AIM 1中开发的合成途径进行调整，以使ENT-HB生物碱衍生物具有效力和选择性的提高。所提出的类似物的身份是由三种不同阿片类药物受体的X射线晶体结构指导的。这些类似物的设计旨在加强与结合口袋保守区域中的关键残基（以增加效力）的相互作用，并与仅在阿片受体中发现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ENT-HB生物碱确实对阿片类药物受体具有有效的亲和力。这将对人类健康产生积极影响，因为然后可以将ENT-HB生物碱类似物用作新的探针分子，以识别新的急性疼痛治疗方法。通过适当的修改，这些相同的探针分子也将被证明可用于开发新的药物成瘾治疗方法。