MOR/DOR Heterodimer Antagonists: A Novel Treatment for Opioid Dependence

摘要 每年有数万人死于阿片类药物过量。其中许多人开始服用阿片类药物 止痛。一个关键的治疗目标是减少阿片类药物依赖的发展，要么通过加强 阿片类止痛，因此可以使用较低剂量或通过阻断戒断症状。阿片替代疗法， 其中长效阿片类药物，如美沙酮和丁丙诺啡被有效的短期作用取代 阿片类药物，需要持续给药，在不减少阿片依赖的情况下掩盖阿片类药物的戒断。一个 长期服用阿片类药物会增加脑出血的形成，这一发现提示了潜在的新方法 ？？阿片受体异源二聚体(MDOR)，并干扰这些异源二聚体的信号 似乎可以增强阿片类药物的抗伤害性，减少依赖。这些发现表明，MDOR 拮抗剂可能通过限制阿片类药物耐受性和预防 阿片类药物戒断。我们创造了一系列新的潜在的选择性多肽MDOR拮抗剂来测试这一点 假设。这些新型拮抗剂结合低亲和力的MOR(H-Tyr-Pro-Phe-D1Nal-NH2)和中等亲和力的MoR(H-Tyr-Pro-Phe-D1Nal-NH2) 具有可变长度(15-42个原子)柔性聚酰胺间隔物的亲和力DOR(Tyr-Tic-OH)药效团。我们的 使用放射性配基结合和35S-GTPγ的初步体外数据显示多药耐药有选择性地靶向， 我们得到的最佳化合物D24M的选择性比为~倍。小鼠脑内微量注射D24M 在急性和慢性疼痛模型中选择性增加阿片类药物的抗伤害性，同时强烈减少 吗啡戒断。这些初步发现表明，D24M可以通过以下方式减少阿片依赖 增强阿片类药物的抗伤害性，降低阿片类药物的耐受性，或直接抑制阿片类药物的戒断。虽然 这种全新的配体很有前途，MDOR拮抗剂的疗效和可译性取决于 在没有破坏性副作用的情况下减少依赖的能力。这方面的UG3阶段 应用程序将大力评估D24M减少雄性和雌性小鼠和大鼠依赖的能力。 鼠标模型支持的适应症将使用非常新颖的家用笼轮运行测试进行测试 测定D24M对正常大鼠日常生活功能的影响。有慢性和无慢性的雄性和雌性大鼠 疼痛将被包括在内，以模拟过渡到依赖的疼痛患者的临床情况。如果这些 研究成功地表明，D24M可以减少依赖(UG3的里程碑)，然后是新的 D24M的衍生物可提高MDOR效力、选择性、代谢稳定性和血脑屏障(BBB) 将开发通过糖基化和纳米颗粒制剂进行渗透(UH3相)。最终目标是 开发一种可用于研究新药(IND)的优化药物--使研究和临床测试成为可能。 这些拟议的研究是高风险、高回报的，有一类全新的治疗药物将在 高度创新的啮齿动物行为模型。我们计划评估新型MDOR拮抗剂D24M，以及 开发减少阿片类药物依赖的新药非常适合UG3/UH3机制。

ABSTRACT Tens of thousands of people die each year from opioid overdose. Many of these people began taking opioids for pain. A critical treatment goal is to reduce the development of opioid dependence either by enhancing opioid analgesia so lower doses can be used or by blocking withdrawal symptoms. Opioid substitution therapy, in which long-lasting opioids such as methadone and buprenorphine are substituted for potent short acting opioids, requires continuous administration to mask opioid withdrawal without reducing opioid dependence. A potentially new approach is suggested by the finding that chronic opioid administration increases the formation of the mu-delta opioid receptor heterodimer (MDOR), and disrupting signaling from these heterodimers appears to enhance opioid antinociception and reduce dependence. These findings suggest that an MDOR antagonist may be especially effective in reducing dependence by limiting opioid tolerance and preventing opioid withdrawal. We created a novel series of potential selective peptide MDOR antagonists to test this hypothesis. These novel antagonists connect low affinity MOR (H-Tyr-Pro-Phe-D1Nal-NH2) and moderate affinity DOR (Tyr-Tic-OH) pharmacophores with a variable length (15-42 atom) flexible polyamide spacer. Our preliminary in vitro data using radioligand binding and 35S-GTPγS shows selectively targeting of the MDOR, with a selectivity ratio of ~89 fold for our best compound, D24M. Microinjection of D24M into the mouse brain selectively increased opioid antinociception in models of acute and chronic pain while strongly decreasing morphine withdrawal. These preliminary findings suggest that D24M could reduce opioid dependence by enhancing opioid antinociception, reducing opioid tolerance, or directly inhibiting opioid withdrawal. Although this completely new class of ligand is promising, the efficacy and translatability of MDOR antagonists depends on the ability to reduce dependence in the absence of disruptive side effects. The UG3 phase of this application will vigorously assess the ability of D24M to reduce dependence in male and female mice and rats. Indications supported by mouse models will be tested using the highly novel home cage wheel-running test in rats to determine the effect of D24M on normal daily function. Male and female rats with and without chronic pain will be included to mimic the clinical situation of pain patients who transition to dependence. If these studies are successful in showing that the D24M can reduce dependence (the UG3 milestone), then new derivatives of D24M to improve MDOR potency, selectivity, metabolic stability, and blood-brain barrier (BBB) penetration via glycosylation and nanoparticle formulation will be developed (UH3 phase). The ultimate goal is to develop an optimized drug ready for Investigational New Drug (IND)-enabling studies and clinical testing. These proposed studies are high-risk, high-reward, with a brand new class of therapeutic drugs to be tested in highly innovative rodent behavioral models. Our plan to assess D24M, the novel MDOR antagonist, and develop new drugs to reduce opioid dependence is well suited to the UG3/UH3 mechanism.