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.

项目摘要 阿片类药物危机产生了无数的健康后果，包括增加使用阿片类药物的发病率 疾病（OUD），这是由于身体和心理障碍升级而表现出来的。药物- 辅助治疗（MAT）有助于降低死亡率，阿片类药物的戒断，摄入量和阿片类药物的行为，因此 实质上改善了从OUD成功恢复的几率，尤其是与社会心理 干预措施。当前基于阿片类药物的垫子（即丁丙诺啡）是正确管理 OUD患者，但是需要增加OUD治疗的武器库。 “非 - 经典的“ Noctpin受体（NOPR）结合内源性神经肽Nocteptin/Orphanin FQ（N/OFQ）， 以唤起伤害感受的效率命名。强大的证据支持N/OFQ-NOPR轴在 酒精的奖励作用以及NOPR配体在酒精使用障碍中的治疗潜力。少是 在OUD中建立了有关该系统的，已发表的文献在调节中实现了NOPR功能 阿片类药物的有益和动机作用。建立在涉及大脑N/OFQ-NOPR轴的前提下 在与Oud相关的行为中，我们与Blackthorn Therapeutics合作评估了他们的小说和选择性 NOPR拮抗剂BTRX-246040作为潜在的OUD治疗。在此UG3中，我们将评估BTRX-246040至 阻止羟考酮的摄入量，而无需滥用责任并抑制羟考酮的戒断和类似救济的行为 在男性和雌性大鼠中。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以及雄性和雌性大鼠的脑甲状腺能力之间。实现 UG3里程碑，我们将在非治疗中进行1阶段临床试验，以寻求UH3的OUD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 BTRX-246040之后的口服羟考酮的DMPK曲线，并轻松抑制阿片类药物的渴望和吸毒 在Oud参与者中。 UH3阶段的第二个目标是开发临床前数据以支持潜在客户 该BTRX-246040可以用作可调节的丁丙诺啡垫。这些对NOPR的调查 UG3/UH3中的拮抗剂BTRX-246040将提高前景，以验证一种新型的OUD药物。