Development of a Novel Class for Opioid Drugs

新型阿片类药物的开发

• 批准号: 8198849
• 负责人: LUDA DIATCHENKO
• 金额: $ 33.62万
• 依托单位: ALGYNOMICS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198849
• 关键词: Absence of pain sensation; Accounting; Adenylate Cyclase; Adverse effects; Affinity; Agonist; Analgesics; Area; Binding; Biochemical; Bioinformatics; Biological; Biological Assay; Cells; Cellular Assay; Chemicals; Clinical; Code; Computer Simulation; Couples; Cyclic AMP; Data; Dependence; Development; Dose; Exons; Exposure to; Future; G-Protein-Coupled Receptors; G-substrate; GTP-Binding Proteins; Genetic; Genetic Variation; Goals; Human; Hyperalgesia; Hypersensitivity; Immunoprecipitation; Ion Channel; Lead; Libraries; Ligand Binding; Mediating; Methods; Modeling; Molecular; Molecular Target; Morphine; Nitric Oxide; Nociception; Opiate Addiction; Opiates; Opioid; Opioid Analgesics; Opioid Receptor; Pain; Pathway interactions; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacology; Phase; Physiological; Preparation; Production; Property; Protein Isoforms; RNA Splicing; Receptor Gene; Receptor Signaling; Relative (related person); Research; Research Design; Screening procedure; Second Messenger Systems; Signal Pathway; Signal Transduction; Site-Directed Mutagenesis; Stimulus; Structural Models; Structure; Surface; Synaptic Transmission; System; Testing; Validation; Variant; base; clinical efficacy; comparative; data mining; experience; in vivo; inward rectifier potassium channel; molecular dynamics; mu opioid receptors; multidisciplinary; novel; overexpression; pre-clinical; radioligand; receptor; research study; response; second messenger; stem; virtual; voltage

DESCRIPTION (provided by applicant): The mu-opioid receptor (MOR) is the primary target for opioid analgesics. While opioids are the most frequently used and effective analgesics for the treatment of moderate to severe clinical pain, their prolonged use leads to reduced efficacy and a number of adverse side effects, including post dosing-induced hyperalgesia and analgesic tolerance. MOR induces analgesia through several mechanisms including the inhibition of second messenger pathways and modulation of ion channel activity. Nevertheless, the opposite, opioid induced cellular excitation, has also been demonstrated and proposed to mediate reductions in efficacy, tolerance, and opioid-induced hyperalgesia following the exposure to opioids. While an array of mechanisms has been advanced that contribute to these use-dependence changes in MOR-mediated effects, we have recently identified a novel mechanism underlying the shift in MOR signaling: a MOR splice variant encoding a functional 6 transmembrane (6TM) receptor. This 6TM isoform was identified in a study designed to determine the genetic basis for variability in sensitivity to exogenous opiates. Importantly, morphine exposure to cells overexpressing the 6TM receptor isoform leads to excitatory cellular effects rather than the classic inhibitory effects that are produced by stimulating the canonical 7TM MOR isoform. The discovery of this new alternative 6TM isoform, which evokes responses that oppose the biological effects of the major 7TM isoform, provides a unique opportunity to identify pharmacological probes that will further our understanding of the mechanisms that mediate the pharmacodynamic effects of opioids and will enable the future development of new opioid compounds that show 7TM agonist and/or 6TM antagonist properties providing high analgesic efficacy with a diminished ability to produce post dosing-induced hyperalgesia, analgesic tolerance, and unwanted physiological side effects. To take maximal advantage of this opportunity, an interdisciplinary investigative team with unique, but complementary, areas of expertise has been assembled to develop, validate and characterize the in silico models of the major 7TM and alternative 6TM receptor isoforms can be used to identity putative isoform selective compounds. The long-term goal of this effort is to develop novel opioids that evoke high potency analgesia without deleterious short- or long-term consequences. PUBLIC HEALTH RELEVANCE: While opioids are the most frequently used and effective analgesics for the treatment of moderate to severe clinical pain, their prolonged use leads to a number of treatment limiting side-effects in a large percentage of patients. An experienced multidisciplinary investigative team proposes a set of studies that have derived from new data on the molecular and signaling basis of opioid receptor pharmacology and associated side-effects. These studies will build in silico models of the human 5-opioid receptor isoforms whose activities differentially contribute to the clinical efficacy of opioids and allow identification of novel and potentially a new class of opioid compounds that will show high analgesic properties with a diminished ability to produce opioid-induced hyperalgesia, analgesic tolerance, and unwanted physiological side effects.

描述（由申请人提供）：μ阿片受体（莫尔）是阿片类镇痛药的主要靶点。虽然阿片类药物是治疗中度至重度临床疼痛的最常用和最有效的镇痛药，但其长期使用导致疗效降低和许多不良副作用，包括给药后诱导的痛觉过敏和镇痛耐受。莫尔通过多种机制诱导镇痛，包括抑制第二信使途径和调节离子通道活性。然而，相反的，阿片样物质诱导的细胞兴奋，也已被证明和提出介导的疗效，耐受性，阿片样物质诱导的痛觉过敏暴露于阿片样物质后的减少。虽然一系列的机制已被推进，有助于这些使用依赖性的变化，MOR介导的影响，我们最近确定了一种新的机制，潜在的转变莫尔信号：一个莫尔剪接变异体编码的功能6跨膜（6 TM）受体。在一项旨在确定对外源性阿片类药物敏感性变异性的遗传基础的研究中鉴定了这种6 TM亚型。重要的是，吗啡暴露于过表达6 TM受体同种型的细胞导致兴奋性细胞效应，而不是通过刺激经典的7 TM莫尔同种型产生的经典抑制效应。这种新的替代性6 TM亚型的发现，引起了与主要7 TM亚型的生物学效应相反的反应，提供了一个独特的机会，以确定药理学探针，这将进一步我们的机制，介导阿片类药物的药效学作用的理解，并将使未来的开发新的阿片类化合物，显示7 TM激动剂和/或或6 TM拮抗剂性质，其提供高镇痛功效，同时降低产生给药后诱导的痛觉过敏、镇痛耐受性和不希望的生理副作用的能力。为了最大限度地利用这一机会，一个具有独特但互补的专业知识领域的跨学科研究团队已经组建，以开发，验证和表征主要7 TM和替代6 TM受体亚型的计算机模型，可用于识别推定的亚型选择性化合物。这项工作的长期目标是开发新型阿片类药物，能够产生高效镇痛作用，而不会产生有害的短期或长期后果。 公共卫生关系：虽然阿片类药物是治疗中度至重度临床疼痛最常用和最有效的镇痛剂，但其长期使用在很大比例的患者中导致了许多限制治疗的副作用。一个经验丰富的多学科调查小组提出了一系列研究，这些研究来自阿片受体药理学和相关副作用的分子和信号基础的新数据。这些研究将建立人5-阿片样物质受体亚型的计算机模型，其活性差异性地有助于阿片样物质的临床疗效，并允许鉴定新的和潜在的一类新的阿片样物质化合物，其将显示出高镇痛特性，但产生阿片样物质诱导的痛觉过敏、镇痛耐受性和不希望的生理副作用的能力降低。