Development of a Novel Class for Opioid Drugs

描述（由申请人提供）：mu-阿片受体（MOR）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最常用和最有效的镇痛药，但其长期使用会导致疗效降低和一些不良副作用，包括给药后引起的痛觉过敏和镇痛耐受。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诱导镇痛。然而，相反的，阿片类药物诱导的细胞兴奋，也被证明并提出介导阿片类药物暴露后疗效、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介导效应中的这些使用依赖性变化，但我们最近发现了MOR信号转移的新机制：MOR剪接变体编码功能性6跨膜（6TM）受体。该6TM异构体是在一项旨在确定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，吗啡暴露于过度表达6TM受体异构体的细胞会导致兴奋性细胞效应，而不是通过刺激规范的7TM MOR异构体产生的经典抑制效应。这种新的替代6TM异构体的发现，引发了与主要7TM异构体的生物效应相反的反应，提供了一个独特的机会来识别药理学探针，这将进一步加深我们对介导阿片类药物药效学效应的机制的理解，并将使未来开发出具有7TM激动剂和/或6TM拮抗剂特性的新型阿片类化合物，这些化合物提供了高镇痛效果，同时减少了产生剂量诱导的痛觉过敏、镇痛耐受性和不必要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跨学科研究团队已经聚集在一起，开发、验证和表征主要7TM和替代6TM受体同种异构体的计算机模型，这些模型可用于识别假定的同种异构体选择性化合物。这项工作的长期目标是开发新型阿片类药物，唤起高效镇痛，没有有害的短期或长期后果。

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.