Cyclic Peptides to Treat Cocaine Use Disorder

治疗可卡因使用障碍的环肽

基本信息

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
项目类别：
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

项目摘要

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520万人报告美国使用可卡因，在2020年报告CUD近130万。CUD是一种慢性病复发到寻求可卡因的行为。此外，暴露于应力会导致可卡因渴望增加发现可以预测可卡因依赖性患者中可卡因的复发。不幸的是，那里目前尚无对CUD或应力诱导的CUD增强的批准药理治疗。 Kappa阿片受体（KO）已成为潜在治疗CUD的有希望的靶标。 Kor及其内源性肽激动剂Dynorphins显着调节药物奖励。接触压力增加了dynorphin肽的水平，众所周知可卡因奖励和促进戒毒个人中使用药物的复发。在动物模型中，与Kor拮抗剂的治疗缓解应力引起的可卡因奖励的增强，并防止应力引起的恢复原状扑灭可卡因寻求可卡因的行为，表明kor拮抗剂可以作为新颖用于CUD和应力引起的CUD的治疗剂。我们已经确定了新型的全身性环状肽，它们有选择地拮抗Kor并显示在应激引起的CUD复发的动物模型中，治疗益处。拟议的研究重点这些新型的口服活性肽kor拮抗剂，目的是优化铅环状肽以产生作为CUD和应力诱导的CUD增强的潜在治疗方法的候选人。 UG3阶段由两个具体目的组成：1）进一步表征现有的有前途的类似物合成以前用于潜在发展； 2）对铅循环进行重点的结构修饰为研究UH3阶段准备的肽。将评估类似物的药代动力学特性和体外KOR亲和力，选择性和拮抗剂的效力，并评估了有希望的类似物口服后的kor拮抗剂效力和可卡因奖励模型的体内（条件地点的偏好和静脉自我给药测定）用于预防治疗功效应力引起的可卡因奖励的增强和应力引起的可卡因的恢复寻求行为。 UH3阶段继续这项工作，并包括两个其他特定目标：3）扩大铅环肽的结构活性关系的探索以改善其药代动力学特性并增强体内药理效力，4）执行其他安全性需要将最有希望的化合物推向临床使用的开发。鉴于我们的初步数据的成功确定了有希望的铅环肽kor拮抗剂，我们期望拟议的研究的结尾已将至少一个用于开发的类似物确定为一种潜在的治疗方法库德。

项目成果

期刊论文数量（1）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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)
影响因子：
0
作者：
Scherrer KH;Eans SO;Medina JM;Senadheera SN;Khaliq T;Murray TF;McLaughlin JP;Aldrich JV
通讯作者：
Aldrich JV