Cyclic Peptides to Treat Cocaine Use Disorder

项目摘要/摘要 可卡因使用障碍(CUD)仍然是一个严重的问题，大约有520万人报告 可卡因在美国的使用，2020年有近130万报告的CUD。CUD是一种慢性疾病，发病率很高 吸食可卡因的行为。此外，暴露在压力下会导致对可卡因的渴望增加 它们已经被发现可以预测可卡因依赖患者的可卡因复发。不幸的是，在那里 目前还没有被批准的药物治疗CUD或应激诱导的CUD增强。 Kappa阿片受体(KOR)已成为治疗CUD的潜在靶点。 KOR及其内源性多肽激动剂强啡肽显著调节药物奖赏。暴露于 压力会增加强啡肽的水平，并已知会矛盾地增强可卡因的奖赏和 在戒毒者中促进复吸。在动物模型中，使用KOR拮抗剂治疗 改善应激诱导的可卡因奖赏增强并防止应激诱导的大鼠 杜绝了寻找可卡因的行为，这表明KOR拮抗剂可以作为新的 CUD和应激性CUD的治疗。 我们已经确定了新的具有系统活性的环肽，它们选择性地拮抗KOR并显示 应激诱导的CUD复发动物模型的治疗益处。拟议的研究重点是 这些新颖的口服活性多肽KOR拮抗剂的目标是优化铅环肽以产生 作为治疗CUD和应激诱导的CUD增强的潜在治疗方法，有可能进一步开发。 UG3阶段包括两个具体目标：1)进一步表征现有的有希望合成的类似物 以前的潜在开发；以及2)对前导循环进行有针对性的结构修改 多肽正在为UH3阶段的研究做准备。将评估类似物的药代动力学 性质和体外KOR亲和力、选择性和拮抗剂效力，有希望的类似物在 口服KOR拮抗剂的体内效力及对可卡因奖赏的动物模型 (条件性位置偏爱和静脉自身给药试验)对预防 应激诱导的可卡因奖赏增强和应激诱导的熄灭可卡因的复燃- 寻求行为。UH3阶段继续这项工作，并包括两个额外的具体目标：3) 拓展铅环肽构效关系的探索，改进其构效关系 体内药代动力学特性和增强药理效力，以及4)执行额外的安全性 需要进行研究，以推动最有希望的化合物进入临床使用的开发。给定 我们的初步数据成功识别出有希望的环肽KOR拮抗剂，我们预计在 拟议的研究结束时，已确定至少有一种类似物可作为一种潜在的治疗方法 丘德。

PROJECT SUMMARY/ABSTRACT Cocaine use disorder (CUD) remains a serious problem, with approximately 5.2 million people reporting cocaine use in the U.S. and nearly 1.3 million reporting CUD in 2020. CUD is a chronic disorder with high rates of relapse to cocaine-seeking behavior. Moreover, exposure to stress induces increases in cocaine craving which have been found to predict relapse to cocaine use in cocaine-dependent patients. Unfortunately, there are currently no approved pharmacological treatments for either CUD or stress-induced potentiation of CUD. Kappa opioid receptors (KOR) have emerged as a promising target for the potential treatment of CUD. KOR and their endogenous peptide agonists, the dynorphins, prominently modulate drug reward. Exposure to stress increases levels of dynorphin peptides and is known to paradoxically potentiate cocaine reward and promote relapse to drug use in abstinent individuals. In animal models, treatment with KOR antagonists ameliorates stress-induced potentiation of cocaine reward and prevents stress-induced reinstatement of extinguished cocaine-seeking behavior, suggesting that KOR antagonists could serve as novel therapeutics for CUD and stress-induced CUD. We have identified novel systemically active cyclic peptides that selectively antagonize KOR and show therapeutic benefits in an animal model of stress-induced relapse to CUD. The proposed research focuses on these novel, orally active peptide KOR antagonists, with the goal of optimizing lead cyclic peptides to yield candidates for further development as potential treatments for CUD and stress-induced potentiation of CUD. The UG3 phase consists of two specific aims: 1) further characterize existing promising analogs synthesized previously for potential development; and 2) perform focused structural modifications on the lead cyclic peptides in preparation for the UH3 phase of the research. Analogs will be assessed for their pharmacokinetic properties and in vitro KOR affinity, selectivity and antagonist potency, with promising analogs evaluated in vivo after oral administration for their KOR antagonist potency and in rodent models of cocaine reward (conditioned place preference and intravenous self-administration assays) for therapeutic efficacy in preventing stress-induced potentiation of cocaine reward and stress-induced reinstatement of extinguished cocaine- seeking behavior. The UH3 phase continues this work and consists of two additional specific aims: 3) expanding the exploration of the structure-activity relationships of the lead cyclic peptides to improve their pharmacokinetic properties and enhance pharmacological potency in vivo, and 4) perform additional safety studies needed to advance the most promising compounds into development for clinical use. Given the success of our preliminary data identifying promising lead cyclic peptide KOR antagonists, we expect at the end of the proposed research to have identified at least one analog for development as a potential treatment of CUD.