NOP Receptor Antagonist for OUD Pharmacotherapy

项目摘要 阿片类药物危机引发了无数的健康后果，包括阿片类药物使用率的增加 疾病（OUD），一种表现为不断升级的身体和心理损伤的病症。药物治疗- 辅助治疗（MAT）有助于降低死亡率、阿片类戒断、摄入和阿片类寻求行为， 大大提高了从OUD中成功康复的几率，特别是当与心理社会因素相结合时， 干预措施。目前基于阿片类药物的MAT（即，丁丙诺啡）是适当管理的主要辅助药物， 然而，对于OUD患者，需要增加OUD的治疗手段。“非- 经典的“痛敏素受体”（NOPr）结合内源性神经肽痛敏素/孤啡肽FQ（N/OFQ）， 因其唤起伤害感受的功效而命名。强有力的证据支持N/OFQ-NOPr轴在 酒精的奖励作用和NOPr配体在酒精使用障碍中的治疗潜力。虽然少， 关于OUD中的该系统建立，已发表的文献暗示NOPr功能在OUD的调节中， 阿片类药物的奖励和激励作用。建立在脑N/OFQ-NOPr轴参与的前提下 在OUD相关行为中，我们与BlackThorn Therapeutics合作，评估他们的新颖性和选择性 NOPr拮抗剂BTRX-246040作为潜在的OUD治疗剂。在本UG 3中，我们将评估BTRX-246040， 阻断羟考酮摄入而无滥用倾向，并抑制羟考酮戒断和复发样行为 在雄性和雌性大鼠中。我们还将确定药物代谢和药代动力学相互作用（DMPK） 羟考酮和BTRX-246040之间的差异以及雄性和雌性大鼠的脑渗透性。随着实现 UG 3里程碑，我们将在UH 3的非寻求治疗的OUD参与者中进行I期临床试验。 相对于安慰剂，我们将确定口服羟考酮后BTRX-246040的安全性和耐受性， BTRX-246040后口服羟考酮的DMPK特征以及抑制阿片类药物渴求和药物喜好的疗效 参加者中。UH 3阶段的第二个目标是开发临床前数据以支持前景 BTRX-246040可以作为丁丙诺啡MAT的佐剂。NOPr的这些调查 拮抗剂BTRX-246040在UG 3/UH 3中的应用将推进验证用于OUD的新型药物的前景。

PROJECT SUMMARY The opioid crisis has spawned a myriad of health consequences, including increased incidence of opioid use disorder (OUD), a condition manifested by escalating physical and psychological impairments. Medication- assisted treatment (MAT) aids in reducing mortality, opioid withdrawal, intake and opioid-seeking behaviors, thus substantially improving the odds of successful recovery from OUD, particularly when coupled with psychosocial interventions. Current opioid-based MAT (i.e., buprenorphine) is a leading adjunct in the proper management of OUD patients, however there is a need to increase the armamentarium of therapeutics for OUD. The “non- classical” nociceptin receptor (NOPr) binds the endogenous neuropeptide nociceptin/orphanin FQ (N/OFQ), named for its efficacy to evoke nociception. Robust evidence supports the role of the N/OFQ-NOPr axis in the rewarding effects of alcohol and the therapeutic potential of NOPr ligands in alcohol use disorder. While less is established regarding this system in OUD, published literature implicates NOPr function in the regulation of the rewarding and motivational effects of opioids. Building on the premise that brain N/OFQ-NOPr axis is involved in OUD-related behaviors, we have partnered with BlackThorn Therapeutics to assess their novel and selective NOPr antagonist BTRX-246040 as a potential OUD therapeutic. In this UG3, we will assess BTRX-246040 to block oxycodone intake without abuse liability and to suppress oxycodone withdrawal and relapse-like behaviors in male and female rats. We will also determine drug metabolism and pharmacokinetics interactions (DMPK) between oxycodone and BTRX-246040 and brain penetrability in male and female rats. With achievement of the UG3 milestones, we will conduct a Phase 1 clinical trial in non-treatment seeking OUD participants in the UH3. Relative to placebo, we will ascertain the safety and tolerability of BTRX-246040 following oral oxycodone, the DMPK profile of oral oxycodone following BTRX-246040, and efficacy to suppress opioid craving and drug-liking in OUD participants. The second goal of the UH3 phase is to develop the preclinical data to support the prospect that BTRX-246040 may serve as an adjuvant to buprenorphine MAT. These investigations with the NOPr antagonist BTRX-246040 in the UG3/UH3 will advance the prospects to validate a novel medication for OUD.