Development of a Novel Class for Opioid Drugs

描述(申请人提供)：Mu-阿片受体(MOR)是阿片类止痛药的主要靶点。虽然阿片类药物是治疗中重度临床疼痛最常用和最有效的止痛药，但长期使用会导致疗效降低和一些副作用，包括剂量后引起的痛敏和止痛耐受。MOR通过抑制第二信使通路和调节离子通道活性等多种机制发挥镇痛作用。然而，相反的，阿片类药物诱导的细胞兴奋，也已经被证明并被提议在阿片类药物暴露后调节有效性、耐受性和阿片类药物诱导的痛觉过敏的降低。虽然已经提出了一系列机制来促进MOR介导的效应的使用依赖变化，但我们最近发现了一种新的机制，其背后的MOR信号转移：一个MOR剪接变异体编码一个功能性的6跨膜(6TM)受体。这一6TM亚型是在一项旨在确定对外源性阿片类药物敏感性变异的遗传基础的研究中确定的。重要的是，吗啡暴露在过度表达6TM受体亚型的细胞中会导致兴奋的细胞效应，而不是通过刺激典型的7TM MOR亚型产生的经典抑制效应。这种新的替代6TM异构体的发现为识别药理探针提供了一个独特的机会，这些探针将促进我们对阿片类药物药效作用机制的理解，并将使新的阿片类化合物的未来发展成为可能，这些阿片化合物显示7TM激动剂和/或6TM拮抗剂的特性提供了高的止痛效果，但产生剂量后诱导的痛觉过敏、止痛耐受和有害的生理副作用的能力减弱。为了最大限度地利用这一机会，已经组建了一个具有独特但互补的专业领域的跨学科研究团队，以开发、验证和表征主要7TM和替代6TM受体异构体的电子模型，可用于鉴定推定的异构体选择性化合物。这一努力的长期目标是开发新的阿片类药物，使其在不产生有害的短期或长期后果的情况下，产生高效的止痛作用。 公共卫生相关性：虽然阿片类药物是治疗中重度临床疼痛最常用和最有效的镇痛剂，但长期使用会导致许多治疗限制了很大比例患者的副作用。一个经验丰富的多学科研究小组提出了一系列研究，这些研究来自阿片受体药理学的分子和信号基础以及相关副作用的新数据。这些研究将建立人类5-阿片受体亚型的电子模型，这些模型的活性对阿片类药物的临床疗效有不同的贡献，并有助于识别新的和潜在的一类新的阿片类化合物，这些化合物将显示出高度的止痛特性，但产生阿片诱导的痛敏、镇痛耐受和有害的生理副作用的能力减弱。

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.