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

摘要 每年有成千上万的人死于阿片类药物过量。这些人中的许多人开始服用阿片类药物 止痛药一个关键的治疗目标是减少阿片类药物依赖的发展， 阿片类镇痛，因此可以使用较低剂量或通过阻断戒断症状。阿片类药物替代疗法， 其中长效阿片类药物如美沙酮和丁丙诺啡替代强效短效阿片类药物， 阿片类药物，需要持续给药，以掩盖阿片类药物戒断，而不减少阿片类药物依赖。一 一种潜在的新方法是通过发现慢性阿片类药物给药增加了 μ-δ阿片受体异二聚体（MDOR），并破坏这些异二聚体的信号传导 似乎增强阿片类抗伤害感受并减少依赖性。这些结果表明，MDOR 拮抗剂通过限制阿片耐受性和预防阿片类药物依赖性， 阿片类药物戒断我们创造了一系列新的潜在的选择性肽MDOR拮抗剂来测试这一点 假说.这些新的拮抗剂将低亲和力莫尔（H-Tyr-Pro-Phe-D1 Nal-NH 2）和中等亲和力MOR（H-Tyr-Pro-Phe-D1 Nal-NH 2）连接在一起。 亲和DOR（Tyr-Tic-OH）药效团与可变长度（15-42个原子）柔性聚酰胺间隔基。我们 使用放射性配体结合和35 S-GTP γS的初步体外数据显示选择性靶向MDOR， 对我们最好的化合物D24 M的选择性比为~89倍。小鼠脑内微量注射D24 M 在急性和慢性疼痛模型中选择性增加阿片类镇痛作用，同时强烈降低 吗啡戒断这些初步研究结果表明，D24 M可以减少阿片类药物依赖， 增强阿片样物质抗伤害感受、降低阿片样物质耐受性或直接抑制阿片样物质戒断。虽然 这类全新的配体是有前途的，MDOR拮抗剂的功效和可翻译性取决于 在没有破坏性副作用的情况下减少依赖的能力。UG 3阶段 本申请将有力地评估D24 M降低雄性和雌性小鼠和大鼠的依赖性的能力。 小鼠模型支持的适应症将使用高度新颖的家庭笼轮运行测试进行测试， 以确定D24 M对正常日常功能的影响。雄性和雌性大鼠，伴和不伴慢性 将包括疼痛以模拟过渡到依赖性的疼痛患者的临床情况。如果这些 研究成功地表明，D24 M可以减少依赖性（UG 3里程碑），然后新的 D24 M衍生物，以改善MDOR效力、选择性、代谢稳定性和血脑屏障（BBB） 将开发通过糖基化的渗透和纳米颗粒制剂（UH 3阶段）。最终目标是 开发一种优化的药物，为新药研究（IND）和临床试验做好准备。 这些拟议中的研究是高风险，高回报的，有一个全新的治疗药物类别进行测试， 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D24 M， 开发新的药物，以减少阿片类药物依赖是非常适合UG 3/UH 3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.