Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics

针对新型阿片类药物使用障碍治疗的 Ghrelin 系统

• 批准号: 9905262
• 负责人: Kathryn A. Cunningham
• 金额: $ 223.03万
• 依托单位: UNIVERSITY OF TEXAS MED BR GALVESTON
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-30 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9905262
• 关键词: Abstinence; Achievement; Adjuvant; Adjuvant Therapy; Agonist; Alcoholic beverage heavy drinker; Alcohols; Analysis of Variance; Attenuated; Behavior; Behavior Therapy; Behavioral; Binding; Brain; Buprenorphine; Chronic; Clinical; Clinical Research; Clinical Trials; Consumption; Coupled; Crystallization; Cues; Data; Development; Disease; Disease model; Dose; Drug Kinetics; Effectiveness; FDA approved; Female; Foundations; Goals; Hormones; Human; Hunger; Hyperactive behavior; Image; Institutes; Intake; Intravenous; Knowledge; Libraries; Ligands; Light; Measures; Medical; Modeling; Morphine; Motivation; National Institute of Drug Abuse; Neuronal Plasticity; Opioid; Opioid Analgesics; Opioid agonist; Oral; Outcome; Oxycodone; Participant; Patients; Pattern; Pharmaceutical Preparations; Pharmacology; Phase; Phenotype; Physiological; Placebos; Process; Publishing; Rattus; Recovery; Relapse; Research; Rewards; Rodent; Safety; Self Administration; Services; Single-Blind Study; Substance Use Disorder; System; Texas; Therapeutic; United States; Universities; Virginia; Visual; Withdrawal; Withdrawal Symptom; Work; addiction; alcohol craving; analog; associated symptom; base; drug metabolism; drug of abuse; experience; ghrelin; growth hormone secretagogue receptor; high throughput screening; improved; intraperitoneal; male; medication-assisted treatment; mortality; mu opioid receptors; non-opioid analgesic; novel; opioid abuse; opioid epidemic; opioid mortality; opioid overdose; opioid use; opioid use disorder; placebo controlled study; pre-clinical; preference; prescription opioid; prescription opioid abuse; psychosocial; response; safety assessment; small molecule; subcutaneous; tool

PROJECT SUMMARY Opioid overdose deaths and the rise in problematic opioid use patterns that indicate the development of opioid use disorder (OUD) have reached crisis levels in the United States. Behavioral interventions coupled with medication-assisted treatment (MAT), such as the partial opioid agonist buprenorphine, reduce repeated opioid overdoses and substantially improve the odds of successful recovery in OUD. While current MAT is a chief adjunct in the proper management of OUD patients, this crisis has crystalized the need to identify novel, non- opioid therapeutics for this chronic medical disorder. Neuroplasticity within the interconnected nodes of the meso-corticostriatal circuit contributes to the enhanced motivational attributes of abused drugs and drug- associated cues, key factors in sustained OUD and relapse. In this light, we identified ghrelin as an endogenous regulator of this therapeutically-relevant circuit. Ghrelin acts by binding to the growth hormone secretagogue receptor 1α (GHS1αR) to transduce several physiological and behavioral processes, including the reward- related effects of opioid agonists. We discovered that systemic administration of a GHS1αR antagonist/inverse agonist dose-dependently attenuated self-administration of the abused opioid analgesic oxycodone as well as oxycodone-seeking. During the UG3 phase, we will leverage this new knowledge and employ a suite of validated rodent OUD models to define the preclinical profile for PF5190457, a selective GHS1αR antagonist/inverse agonist developed by Pfizer which has advanced into clinical trials. We will assess PF5190457 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 the drug metabolism and pharmacokinetics (DMPK) interaction between oxycodone and PF5190457 and brain penetrability of PF5190457 in opioid-experienced rats. With achievement of the UG3 preclinical milestones, we will work with NIDA to partner with Pfizer for Phase 1 clinical studies in non-treatment seeking OUD participants through assessment of the safety and tolerability of PF5190457 following oral oxycodone administration relative to placebo, the DMPK profile of oral oxycodone in OUD participants following PF5190457 (vs. placebo) dosing, and the subjective response to oral oxycodone following PF5190457 (vs. placebo). The second goal of the UH3 phase is to develop the preclinical data to support the prospect that PF5190457 may serve as an adjuvant therapy to reduce the dose of buprenorphine required for MAT. The small molecule GHS1αR antagonist/inverse agonist PF5190457 is a novel target for an OUD medication and achievement of the UG3 milestones demonstrating its effectiveness in the comprehensive preclinical analyses will provide the foundation for the UH3 to characterize PF5190457 as a potential treatment for OUD. The outcomes of the UG3/UH3 will have a sustained, powerful impact in our field with the prospect to validate a novel medication for OUD.

项目总结 阿片类药物过量死亡和表明阿片类药物发展的有问题的阿片类药物使用模式的上升 在美国，使用障碍(OUD)已经达到了危机水平。行为干预加上 药物辅助治疗(MAT)，如部分阿片激动剂丁丙诺啡，减少重复阿片类药物 服药过量，大大提高了乌德康复成功的几率。而现任的麦特是首席 作为乌德患者适当管理的附属品，这场危机明确了识别新的、非 治疗这种慢性疾病的阿片类药物。三叉神经节相互连接的神经可塑性 中脑皮质纹状体环路有助于增强滥用药物和药物的动机属性。 相关线索，持续OUD和复发的关键因素。在这一点上，我们确定Ghrelin是一种内源性 这个与治疗相关的回路的调节器。Ghrelin通过与生长激素促分泌剂结合发挥作用 受体1α(GHS1αR)转导几个生理和行为过程，包括奖赏- 阿片类激动剂的相关效应。我们发现全身给予GHS1αR拮抗剂/反向 激动剂剂量依赖地减弱滥用阿片类止痛剂羟考酮的自身给药以及 寻求羟考酮。在UG3阶段，我们将利用这一新知识并采用一套经过验证的 啮齿动物模型确定选择性GHS1α受体拮抗剂/反向受体拮抗剂PF5190457的临床前特征 辉瑞公司开发的激动剂已进入临床试验。我们将评估PF5190457以阻止 无滥用倾向的羟考酮摄入，并抑制羟考酮戒断和复发样行为 雄鼠和雌鼠。我们还将确定药物代谢和药代动力学(DMPK)的相互作用 羟考酮和PF5190457之间的关系以及PF5190457在阿片类药物经验大鼠中的脑透性。使用 为了实现UG3临床前里程碑，我们将与NIDA合作，与辉瑞合作进行第一阶段临床 通过评估阿司匹林的安全性和耐受性来寻求受试者的非治疗研究 PF5190457口服羟考酮与安慰剂相比，口服羟考酮在 服用PF5190457(与安慰剂相比)后的受试者以及口服羟考酮的主观反应 遵循PF5190457(与安慰剂相比)。UH3阶段的第二个目标是开发临床前数据以支持 PF5190457可作为减少丁丙诺啡用量的辅助治疗的前景 对于垫子。小分子GHS1αR拮抗剂/反向激动剂PF5190457是OUD的新靶点 药物治疗和UG3里程碑的成就证明了其在综合 临床前分析将为UH3将PF5190457表征为潜在的治疗方法提供基础 为了奥德。普遍定期审议/普遍定期审议的结果将在我们的领域产生持续的、强有力的影响，并有望 验证一种新的治疗OUD的药物。