Cyclic Peptides to Treat Cocaine Use Disorder

治疗可卡因使用障碍的环肽

• 批准号: 10688637
• 负责人: Jane V Aldrich
• 金额: $ 94.55万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-15 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10688637
• 关键词: ABCB1 gene; Acute; Affinity; Agonist; Animal Model; Behavior; Behavioral; Behavioral Assay; Binding Proteins; Biological Assay; Cell model; Cells; Chemosensitization; Chronic; Chronic Disease; Clinical Trials; Cocaine; Cocaine use disorder; Cyclic Peptides; Data; Development; Disease; Drug Kinetics; Drug Modulation; Drug usage; Dynorphins; Evaluation; Exposure to; Generations; Goals; In Vitro; Individual; Intravenous; Lead; Ligands; Liver; Medical; Metabolism; Modeling; Modification; Mus; Neurosciences; Opioid; Opioid Antagonist; Opioid Receptor; Opioid Receptor Binding; Oral; Oral Administration; Overdose; Patients; Peptides; Permeability; Persons; Pharmacological Treatment; Pharmacology; Phase; Plasma Proteins; Positioning Attribute; Preparation; Property; Receptor Activation; Relapse; Reporting; Research; Research Personnel; Rodent Model; Self Administration; Stress; Structure-Activity Relationship; Testing; Therapeutic; Treatment Efficacy; Work; analog; antagonist; blood-brain barrier crossing; candidate identification; clinical development; cocaine craving; cocaine reward; cocaine seeking; cocaine use; conditioned place preference; design; drug craving; drug discovery; drug reward; improved; in vitro activity; in vivo; in vivo evaluation; kappa opioid receptors; lead optimization; mimetics; monolayer; mouse model; novel; novel therapeutics; pharmacologic; preclinical evaluation; prevent; relapse prediction; safety study; success

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.

项目总结/摘要 可卡因使用障碍（CUD）仍然是一个严重的问题，约有520万人报告 可卡因在美国的使用和近130万报告CUD在2020年。CUD是一种慢性疾病， 毒瘾复发的几率此外，暴露在压力下会导致对可卡因的渴望增加 已发现其预测可卡因依赖患者中可卡因使用的复发。可惜 目前还没有批准的药物治疗CUD或应激诱导的CUD增强。 κ阿片受体（KOR）已成为一个有前途的目标，为潜在的治疗CUD。 KOR及其内源性肽激动剂强啡肽显著调节药物奖赏。暴露于 应激增加强啡肽的水平，并且已知矛盾地增强可卡因奖赏， 促进戒毒者复吸。在动物模型中，用KOR拮抗剂治疗 改善应激诱导的可卡因奖赏增强，并防止应激诱导的可卡因奖赏恢复。 消除了寻求可卡因的行为，这表明KOR拮抗剂可以作为新型药物 治疗CUD和应激诱导的CUD。 我们已经鉴定了选择性拮抗KOR的新型全身活性环肽， 压力诱导的CUD复发动物模型的治疗益处。拟议的研究重点是 这些新的口服活性肽KOR拮抗剂，目的是优化先导环肽， 作为CUD的潜在治疗和应激诱导的CUD增强的进一步开发的候选者。 UG 3阶段包括两个具体目标：1）进一步表征现有的有希望的合成类似物 先前用于潜在开发;以及2）对先导循环进行重点结构修饰 为研究的UH 3阶段做准备。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， 口服给药后的体内KOR拮抗剂效力和可卡因奖励的啮齿动物模型 （条件性位置偏爱和静脉内自我给药测定），用于预防 应激诱导可卡因奖赏增强和应激诱导的可卡因消退恢复- 寻求行为。UH 3阶段继续这项工作，并包括两个额外的具体目标：3） 扩大先导环肽的结构-活性关系的探索，以改善其 药代动力学特性和增强体内药理学效力，以及4）执行额外的安全性 需要进行研究，以推动最有前途的化合物进入临床使用的开发阶段。鉴于 我们的初步数据的成功鉴定有前途的先导环肽KOR拮抗剂，我们预计在 在拟议的研究结束时，已确定至少一种类似物用于开发，作为潜在的治疗方法。 CUD。

项目成果

Tryptophan Substitution in CJ-15,208 (cyclo[Phe-D-Pro-Phe-Trp]) Introduces δ-Opioid Receptor Antagonism, Preventing Antinociceptive Tolerance and Stress-Induced Reinstatement of Extinguished Cocaine-Conditioned Place Preference.

• DOI: 10.3390/ph16091218
• 发表时间: 2023-08-29
• 期刊: Pharmaceuticals (Basel, Switzerland)
• 作者: Scherrer KH;Eans SO;Medina JM;Senadheera SN;Khaliq T;Murray TF;McLaughlin JP;Aldrich JV
• 通讯作者: Aldrich JV