NOP Receptor Antagonist for OUD Pharmacotherapy

用于 OUD 药物治疗的 NOP 受体拮抗剂

• 批准号: 10085851
• 负责人: Kathryn A. Cunningham
• 金额: $ 279.38万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10085851
• 关键词: Abstinence; Achievement; Adjuvant; Alcohols; Behavior; Binding; Biological Assay; Brain; Buprenorphine; Clinical; Clinical Research; Collaborations; Coupled; Cues; Data; Disease; Disease model; Drug Kinetics; Effectiveness; Electrocardiogram; Female; Foundations; Genes; Goals; Health; Image; Impairment; Incidence; Institutes; Institution; Intake; Intervention; Intravenous; Investigation; Investigational Drugs; Lifestyle-related condition; Ligands; Literature; Mediating; Medical; Mental Depression; Motivation; Names; Neuropeptides; Nociception; ORL1 receptor; Opioid; Opioid Antagonist; Opioid Receptor; Opioid agonist; Oral; Outcome; Oxycodone; Participant; Patients; Pharmaceutical Preparations; Pharmacologic Actions; Pharmacotherapy; Phase; Phase I Clinical Trials; Phenotype; Placebos; Publishing; Rattus; Recovery; Regulation; Relapse; Research; Rewards; Rodent; Role; Safety; Self Administration; Services; Substance Use Disorder; System; Texas; Therapeutic; United States; Universities; Virginia; Visual; Withdrawal; Withdrawal Symptom; addiction; alcohol effect; alcohol use disorder; analog; base; craving; drug discrimination; drug metabolism; improved; in vivo; innovation; intraperitoneal; kappa opioid receptors; male; medication-assisted treatment; mortality; mu receptors; nociceptin; novel; opioid abuse; opioid epidemic; opioid misuse; opioid overdose; opioid use disorder; opioid withdrawal; phase 1 study; pre-clinical; prescription opioid; psychologic; psychosocial; receptor binding; receptor function; small molecule; subcutaneous

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.

项目总结 阿片类药物危机引发了无数健康后果，包括阿片类药物使用率增加。 精神障碍(OUD)，一种表现为身体和心理损伤不断加剧的状况。药物治疗- 辅助治疗(MAT)有助于减少死亡率、阿片类药物戒断、摄取和寻找阿片类药物的行为，因此 显著提高成功康复的几率，特别是在与心理社会相结合的情况下 干预措施。目前以阿片类药物为基础的MAT(即丁丙诺啡)是正确管理 然而，对于OUD患者，有必要增加OUD的治疗手段。“非-- 经典的“伤害素受体”(NOPR)与内源性神经肽伤害素/孤啡肽FQ(N/OFQ)结合， 因其唤起伤害感的功效而得名。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。而更少的是 在OUD中关于这一系统的建立，发表的文献暗示NOPR在调节 阿片类药物的奖赏和激励作用。建立在大脑N/OFQ-NOPR轴参与的前提下 在与OUD相关的行为方面，我们与黑刺治疗公司合作，评估他们的新颖性和选择性 NOPR拮抗剂btrx-246040是一种潜在的治疗药物。在本UG3中，我们将评估BTRX-246040以 阻断羟考酮摄入而无滥用倾向，并抑制羟考酮戒断和复发行为 在雄性和雌性大鼠身上。我们还将确定药物代谢和药代动力学相互作用(DMPK) 羟考酮和溴氰菊酯-246040之间的关系以及雄性和雌性大鼠的脑穿透性。随着实现了 根据UG3的里程碑，我们将进行一项非治疗的第一阶段临床试验，寻找UH3的参与者。 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 羟考酮口服给药后的DMPK谱及抑制阿片类药物渴求和药物依赖的疗效 在受试者中。UH3阶段的第二个目标是开发支持前景的临床前数据 BTRX-246040可作为丁丙诺啡垫佐剂。这些与NOPR的调查 UG3/UH3中的拮抗剂Btrx-246040将为验证OUD的新药提供前景。