Deterrents for prescription opioid abuse

项目摘要 MU阿片受体(MOR)激动剂是治疗中重度急性发作最有效的药物 疼痛，但它们高度的滥用倾向和致命过量的风险给公众造成了巨大的损失 最近几年的健康状况。我们的研究计划已经调查了将MOR 含kappa阿片受体(KOR)激动剂的激动剂可阻止滥用并促进止痛 效果。我们在该项目第一阶段的发现表明，非典型的KOR激动剂， 呋喃芬，减少羟考酮的滥用相关影响，并增强镇痛，但 它本身也产生了显著的镇静作用。最近，新的KOR激动剂已经被 据报道，它们产生的不良行为影响甚至更少，这是典型的 属于KOR-激动剂类别。这些非典型的KOR激动剂被描述为“偏重G蛋白” 这是因为与KOR的其他途径相比，它们激活G蛋白信号的能力更强。我们的 初步数据表明，有偏向的KOR激动剂三氮唑1.1在治疗上更具选择性 比那呋喃芬好。然而，目前尚不清楚三氮唑1.1观察到的阳性特征是否 由于G蛋白偏向或结构类特有的其他潜在机制。总目标 这一续期应用的目的是系统地研究羟考酮与新的 非典型的KOR激动剂，据报道是来自不同结构类别的G蛋白偏向于 确定报告的信号偏差是否与治疗选择性增加(减少)相关 潜在的滥用；增强的抗伤害性)和减少KOR介导的“副作用”。要完成 这个目标，我们将使用互补的动物模型(恒河猴和大鼠)和严谨 定量药理学以确定非典型KOR激动剂是否可以减少羟考酮的滥用- 相关效应(特定目标1)，增强羟考酮的止痛效果(目标2)，并产生 与羟考酮联合使用时副作用更少(目标3)。我们将介绍 各种KOR激动剂，产生治疗性和不良副作用，以确定治疗的最佳线索 激活MORS和KORS(双作用分子；药物)的治疗学的未来发展 组合)。这次更新建议的研究将对公众健康产生积极影响，因为 为开发非成瘾止痛药奠定基础，使其保持较高的治疗水平 当前处方阿片类药物的疗效。

Project Summary Mu opioid receptor (MOR) agonists are the most effective treatments for moderate to severe acute pain, but their high abuse liability and risk for lethal overdose have exacted a significant toll on public health in recent years. Our program of study has investigated the feasibility of combining MOR agonists with kappa opioid receptor (KOR) agonists to deter abuse and enhance pain-decreasing effects. Our findings from Project Period 1 of this program indicate that the atypical KOR agonist, nalfurafine, decreases oxycodone’s abuse-related effects and enhances analgesia, but nalfurafine also produced significant sedative effects on its own. Recently, new KOR agonists have been developed that are reported to produce even fewer of the adverse behavioral effects that are typical of the KOR-agonist class. These atypical KOR agonists have been described as “G-protein biased” due to their greater potency to activate G-protein signaling relative to other pathways at the KOR. Our preliminary data indicate that the biased KOR agonist, triazole 1.1, is more therapeutically selective than nalfurafine. However, it is unknown if the positive characteristics observed with triazole 1.1 are due to G-protein bias or other potential mechanisms peculiar to the structural class. The overall goal of this renewal application is to systematically investigate combinations of oxycodone with new atypical KOR agonists that are reported to be G-protein biased from different structural classes to determine if reported signaling bias is associated with increased therapeutic selectivity (decreased abuse potential; enhanced antinociception) and reduced KOR-mediated “side effects”. To accomplish this goal, we will use complementary animal models (rhesus monkeys and rats) and rigorous quantitative pharmacology to determine if the atypical KOR agonists can reduce oxycodone’s abuse- related effects (Specific Aim 1), augment oxycodone’s pain-decreasing effects (Aim 2), and produce fewer side effects when combined with oxycodone (Aim 3). We will relate the relative potencies of the various KOR agonists to produce therapeutic and unwanted side effects to identify optimal leads for future development of therapeutics that activate MORs and KORs (dual-acting molecules; drug combinations). The studies proposed in this renewal will positively impact public health by laying the groundwork for the development of non-addictive pain medications that will retain the high treatment efficacy of current prescription opioids.