Targeting the Ghrelin System for Novel Opioid Use Disorder Therapeutics

项目摘要 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增加 使用障碍（OUD）在美国已达到危机水平。行为干预加上 药物辅助治疗（MAT），如部分阿片类激动剂丁丙诺啡，减少重复阿片类 过量并大大提高了OUD成功恢复的几率。虽然目前的MAT是一个首席 在OUD患者的适当管理的辅助，这场危机已经结晶需要确定新的，非 阿片类药物治疗这种慢性疾病。神经可塑性内的互连节点的 中皮质纹状体回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。鉴于此，我们将生长激素释放肽鉴定为内源性 这个治疗相关回路的调节器。生长激素释放肽通过与生长激素促分泌素结合而起作用 受体1α（GHS 1 αR）参与多种生理和行为过程，包括奖赏- 阿片类激动剂的相关作用。我们发现全身给予GHS 1 αR拮抗剂/逆转录酶抑制剂， 激动剂剂量依赖性减弱滥用阿片类镇痛药羟考酮的自我给药，以及 寻求羟考酮在UG 3阶段，我们将利用这些新知识，并采用一套经过验证的 啮齿类动物OUD模型，以确定PF 5190457（一种选择性GHS 1 αR拮抗剂/反向剂）的临床前特征 辉瑞公司开发的激动剂，已进入临床试验阶段。我们将评估PF 5190457以阻止 羟考酮摄入无滥用倾向，并抑制羟考酮戒断和复发样行为 雄性和雌性大鼠。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PF 5190457之间的关系以及PF 5190457在阿片类药物经验大鼠中的脑渗透性。与 为了实现UG 3临床前里程碑，我们将与NIDA合作，与辉瑞合作进行1期临床试验， 在非寻求治疗的OUD受试者中进行的研究，通过评估 PF 5190457口服羟考酮给药后相对于安慰剂， PF 5190457（vs.安慰剂）给药后的OUD受试者以及对口服羟考酮的主观反应 PF 5190457（vs.安慰剂）后。UH 3阶段的第二个目标是开发临床前数据， PF 5190457可能作为一种辅助治疗，以减少所需丁丙诺啡剂量的前景 关于MAT小分子GHS 1 αR拮抗剂/反向激动剂PF 5190457是OUD的新靶点 药物和UG 3里程碑的实现，证明其在综合治疗中的有效性 临床前分析将为UH 3将PF 5190457表征为潜在治疗提供基础 对于OUD。UG 3/UH 3的成果将在我们的领域产生持续的、强大的影响，其前景是 验证一种治疗OUD的新药。

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.