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.

项目摘要 阿片类药物过量死亡和有问题的阿片类药物使用模式的增加，表明阿片类药物的发展 使用障碍（OUD）在美国达到了危机水平。行为干预与 药物辅助治疗（MAT），例如部分阿片类动力学丁丙诺啡，减少了反复的阿片类药物 过量服用并大大提高了OUD成功恢复的几率。虽然当前的垫子是首席 在适当管理OUD患者的辅助状态下，这场危机已经确定了识别新颖的，非 - 这种慢性医学障碍的阿片类药物疗法。在互连节点内的神经塑性 中质纹状体回路有助于提高滥用药物和药物的动机属性 相关线索，持续Oud和继电器的关键因素。在这种情况下，我们将生长素释放为内源性 生长素通过与成长的horsene secretagogue结合起来的作用 受体1α（GHS1αR）翻译几个物理和行为过程，包括奖励 - 阿片类动力学家的相关作用。我们发现全身给药GHS1αR拮抗剂/逆 激动剂剂量依赖性地减弱了滥用阿片类镇痛羟考酮的自我给药 寻求羟考酮。在UG3阶段，我们将利用这一新知识，并雇员一套经过验证的套件 定义PF5190457的临床前轮廓的啮齿动物OUD模型，一种选择性GHS1αR拮抗剂/逆逆转录 由辉瑞开发的激动剂已进入临床试验。我们将评估PF5190457以阻止 羟考酮的摄入量无滥用责任并抑制羟考酮的戒断和类似于缓解的行为 雄性和雌性老鼠。我们还将确定药物代谢和药代动力学（DMPK）相互作用 在阿片类药物经验的大鼠中，羟考酮和PF5190457与PF5190457的大脑渗透性之间。和 达到UG3临床前里程碑的实现，我们将与NIDA合作与辉瑞合作进行1期临床 通过评估的安全性和耐受性，在非治疗中寻求OUD参与者的研究 口服羟考酮的PF5190457相对于安慰剂，口服羟考酮的DMPK曲线 OUD参与者PF5190457（相对于安慰剂）剂量，以及对口服羟考酮的主观反应 遵循PF5190457（vs.安慰剂）。 UH3阶段的第二个目标是开发临床前数据以支持 PF5190457可以作为可调节疗法的前景，以减少所需的丁丙诺啡剂量 格式。小分子GHS1αR拮抗剂/逆激动剂PF5190457是OUD的新目标 UG3里程碑的药物和成就，证明了其在综合中的有效性 临床前分析将为UH3提供将PF5190457表征为潜在治疗的基础 对于Oud。 UG3/UH3的结果将对我们的领域产生持续，强大的影响，并有前景 验证一种新颖的Oud药物。