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Development of Novel Opioid Peptides for Cocaine Abuse

用于可卡因滥用的新型阿片肽的开发

基本信息

批准号：
8432009
负责人：
Jane V Aldrich
金额：
$ 64.61万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-03-01 至 2015-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8432009
关键词：
Advanced Development Affinity Agonist Animals Behavior Behavioral Biological Assay Biological Factors Blood Brain Caco-2 Cells Chronic Clinical Clinical Research Clinical Trials Design Cocaine Cocaine Abuse Cocaine Dependence Cocaine Users Cutaneous Administration Cyclic Peptides Data Development Disease Dopamine Dose Drug Interactions Drug Kinetics Drug abuse Dynorphins Evaluation Exhibits Exposure to FDA approved Family Funding Goals Hour Human Illicit Drugs In Vitro Individual Laboratories Lead Liver Microsomes Maintenance Mediating Medical Modeling Mus Neurotransmitters Opioid Peptide Opioid Receptor Oral Administration Oryctolagus cuniculus Penetration Peptide Synthesis Peptides Pharmaceutical Preparations Pharmacodynamics Pre-Clinical Model Preparation Property Public Health Relapse Reporting Research Research Personnel Resistance Rewards Rodent Rodent Model Self Administration Signal Transduction Smooth Muscle Societies Stress Structure Structure-Activity Relationship Testing Therapeutic Therapeutic Agents Treatment Efficacy Uncertainty Vas deferens structure addiction analog base cocaine relapse prevention craving design dopamine transporter drug of abuse drug seeking behavior effective therapy improved in vitro Assay in vivo kappa opioid receptors monolayer neurotoxicity neurotransmitter reuptake nonhuman primate norbinaltorphimine novel peptide structure phenylalanylphenylalanine pre-clinical preclinical study preference prevent receptor research study response small molecule therapeutic development tryptophyl-proline

项目摘要

DESCRIPTION (provided by applicant): Drug abuse/addiction is a serious, chronically relapsing clinical condition with grave consequences for both individuals and public health. Cocaine is a major illicit drug of abuse, with over 5 million cocaine users in the U.S., yet there are no medications currently approved for the treatment of cocaine abuse and addiction. Thus, there is a pressing need to examine and develop new medical entities (NME) as therapeutics for the treatment of cocaine abuse and addiction. Cocaine enhances the signaling of dopamine, a neurotransmitter associated with the rewarding effects of this drug. Kappa opioid receptors (KOR) and their endogenous peptide agonists the dynorphins prominently modulate dopaminergic function. Moreover, dynorphin signaling is implicated in the response to stress, a key factor in the reinstatement of extinguished drug seeking behavior. Selective KOR antagonists can prevent stress-induced reinstatement of cocaine-seeking behavior in animal studies, and therefore have potential as maintenance medications to prevent relapse to cocaine abuse. However, the known nonpeptide selective KOR antagonists exhibit exceptionally long durations of activity (i.e. weeks after a single dose) which could complicate their therapeutic development. Thus, novel selective KOR antagonists with more finite durations of action could be important lead compounds for further development as potential therapeutic agents. We have identified a novel small cyclic peptide that selectively antagonizes KOR for a finite duration (hours) and prevents stress-induced reinstatement of extinguished cocaine-seeking behavior after oral administration. This cyclic peptide represents an important lead compound for the development of agents for the treatment of cocaine addiction and relapse to cocaine abuse. This proposal brings together a team of researchers with highly synergistic expertise to advance the development of this novel lead cyclic peptide, from the design and synthesis of analogs through their evaluation in preclinical models as potential treatments for cocaine addiction. The proposed research involves four specific aims: 1) the synthesis of analogs of the lead cyclic peptide and verification in initial in vitro assays of their KOR affinity, selectivity, antagonist activity and lack of neurotoxicity; 2) initial pharmacological evaluation in vivo in assays of agonist-induced antinociception in rodents to define KOR antagonist activity of the novel peptides, and analysis of their pharmacokinetic properties in vitro; 3) in vivo evaluation in rodent models of reward (conditioned place preference and self-administration assays) for therapeutic efficacy in preventing reinstatement of extinguished cocaine-seeking behavior, alongside tests for possible undesirable somatic and behavioral effects, and in vivo pharmacokinetic analysis; and 4) pharmacodynamic and pharmacokinetic analysis of optimized candidates in non-human primates, as a crucial translational step for support of potential later regulatory-based studies. This research is expected to produce candidates that can be rationally and productively advanced into late preclinical development as potential treatments for cocaine addiction and relapse.

描述（由申请人提供）：药物滥用/成瘾是一种严重的、慢性复发的临床病症，对个人和公共健康造成严重后果。可卡因是一种主要的非法滥用药物，美国有超过 500 万可卡因使用者，但目前还没有批准用于治疗可卡因滥用和成瘾的药物。因此，迫切需要检查和开发新的医疗实体（NME）作为治疗可卡因滥用和成瘾的疗法。可卡因增强多巴胺的信号传导，多巴胺是一种与该药物的奖励作用相关的神经递质。 Kappa 阿片受体 (KOR) 及其内源性肽激动剂强啡肽显着调节多巴胺能功能。此外，强啡肽信号传导与对压力的反应有关，这是恢复已消失的药物寻求行为的关键因素。在动物研究中，选择性 KOR 拮抗剂可以防止应激引起的可卡因寻求行为的恢复，因此有可能作为维持药物来防止可卡因滥用复发。然而，已知的非肽选择性 KOR 拮抗剂表现出异常长的活性持续时间（即单剂量后数周），这可能会使它们的治疗开发复杂化。因此，具有更有限作用持续时间的新型选择性 KOR 拮抗剂可能是进一步开发为潜在治疗剂的重要先导化合物。我们发现了一种新型的小环肽，它可以在有限的持续时间内（数小时）选择性地拮抗 KOR，并防止口服给药后应激诱导的已消失的可卡因寻求行为的恢复。这种环肽代表了用于开发治疗可卡因成瘾和可卡因滥用复发的药物的重要先导化合物。该提案汇集了一组具有高度协同专业知识的研究人员，以推进这种新型先导环肽的开发，从类似物的设计和合成到在临床前模型中对其作为可卡因成瘾的潜在治疗方法的评估。拟议的研究涉及四个具体目标：1）先导环肽类似物的合成，并在初步体外测定中验证其 KOR 亲和力、选择性、拮抗剂活性和无神经毒性； 2) 在啮齿类动物中进行激动剂诱导的抗伤害试验的体内初步药理学评价，以确定新型肽的 KOR 拮抗剂活性，并分析其体外药代动力学特性； 3) 在啮齿动物奖励模型（条件性位置偏好和自我给药测定）中进行体内评估，以防止已消失的可卡因寻求行为恢复的治疗效果，同时测试可能产生的不良躯体和行为效应，以及体内药代动力学分析； 4) 在非人类灵长类动物中对优化候选药物进行药效学和药代动力学分析，作为支持后续潜在的基于监管的研究的关键转化步骤。这项研究预计将产生可合理且有效地进入后期临床前开发的候选药物，作为可卡因成瘾和复发的潜在治疗方法。