Development of a Novel Class for Opioid Drugs

新型阿片类药物的开发

基本信息

批准号：
8451359
负责人：
LUDA DIATCHENKO
金额：
$ 32.08万
依托单位：
ALGYNOMICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-04-01 至 2014-09-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451359
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 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 screening second messenger stem virtual voltage

项目摘要

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.

描述（由申请人提供）：Mu-Apioid受体（MOR）是阿片类镇痛药的主要目标。虽然阿片类药物是用于治疗中度至严重临床疼痛的最常用和有效的镇痛药，但它们的延长使用导致疗效降低和许多不良副作用，包括后给药后诱发的痛苦和镇痛耐受性。 MOR通过几种机制诱导镇痛，包括抑制第二信使途径和离子通道活性的调节。然而，相反的阿片类药物诱导的细胞激发也已被证明并提议介导接触阿片类药物后的疗效，耐受性和阿片类药物诱导的痛觉过敏。尽管已经采取了一系列机制，从而有助于MOR介导的效应的这些使用依赖性变化，但我们最近确定了MOR信号转移转移的基础的新型机制：编码功能6跨膜（6TM）受体的MOR剪接变体。该6TM同工型在一项研究中鉴定出旨在确定对外源性鸦片敏感性变异性的遗传基础。重要的是，过表达6TM受体同工型的细胞的吗啡会导致兴奋性细胞效应，而不是通过刺激规范的7TM MOR同工型产生的经典抑制作用。发现这种新的6TM同工型的发现，唤起了反对主要7TM同工型生物学作用的反应，这提供了一个独特的机会来识别药理学探针，以进一步了解我们对阿片类药物的药态效应的机制的理解，并能够促进7T型和/6型的典型效果，并促进7TM或6型的特性。产生后剂量引起的痛觉过敏，镇痛耐受性和不必要的生理副作用的能力降低。为了获得这一机会的最大优势，已经组装了一个独特但互补的专业领域的跨学科调查团队，以开发，验证和表征主要的7TM的硅模型中，可以将替代6TM受体同工型用于识别性同工型选择性化合物。这项工作的长期目标是开发新型阿片类药物，这些阿片类药物会引起高效力镇痛，而没有有害的短期或长期后果。