Peptidic Kappa Opioid Receptor Ligands as Potential Treatments for Drug Addiction

肽 Kappa 阿片受体配体作为药物成瘾的潜在治疗方法

基本信息

批准号：
7921005
负责人：
Jane V Aldrich
金额：
$ 43.65万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7921005
关键词：
Acute Address Affect Affinity Agonist Animal Model Behavior Biological Availability Blood - brain barrier anatomy Brain Clinical Cocaine Cocaine Abuse Cocaine Users Crime Development Dopamine Dose Drug Addiction Drug Kinetics Drug abuse Dynorphin A Dynorphins Exhibits Exposure to Goals Illicit Drugs In Vitro Individual Lead Ligands Literature Maintenance Mediating Metabolic Metabolism Modeling Modification Mus Neuraxis Neurons Opioid Opioid Receptor Pain Penetration Peptides Pharmaceutical Preparations Positioning Attribute Property Protein Precursors Relapse Research Research Personnel Rewards Self Administration Signal Transduction Stress Structure System Therapeutic Therapeutic Agents Time addiction analog craving design dopamine transporter drug of abuse drug seeking behavior effective therapy improved in vivo kappa opioid receptors kappa(1) opioid receptor meetings neurotoxicity novel peptide analog peptide structure preference prevent prodynorphin programs uptake

项目摘要

DESCRIPTION (provided by applicant): Drug abuse is a serious problem with both individual and societal consequences, and cocaine is a major illicit drug of abuse, with nearly 2 million cocaine users in the U.S. Despite this, there is no medication currently available for the treatment of cocaine abuse and addiction, highlighting an urgent need to examine agents for therapeutic potential in the treatment of cocaine abuse. Cocaine is known to exert its action in part by blocking the dopamine transporter that is responsible for the termination of dopamine signaling, thereby enhancing the dopamine signaling which is thought to be associated with the rewarding effects of this drug. Notably, activation of kappa opioid receptors (KOR) inhibits dopamine signaling, and thus may counteract the effects of cocaine. There is extensive evidence that KOR agonists can acutely suppress cocaine reward and self-administration. Preliminary evidence here demonstrates that a novel peptide KOR agonist suppressed cocaine reward through acute stimulation of the KOR. While this demonstrates the therapeutic value of acute KOR agonists in the treatment of cocaine abuse, repeated treatment with KOR agonists have been paradoxically shown to produce an increase in the rewarding effects of cocaine. Likewise, exposure to stress is a key factor in reinstatement of drug seeking behavior, an effect that may be mediated by activation of the KOR system by the endogenous KOR agonist dynorphin. We hypothesize that peptide KOR antagonists may therefore prevent stress-induced reinstatement. Supporting this, preliminary results here demonstrate that pretreatment with the novel peptide KOR antagonist prevented stress-induced reinstatement of cocaine conditioned place preference, suggesting that KOR antagonists could serve as effective maintenance treatments to prevent a relapse to cocaine abuse. This proposal brings together a highly synergistic team of researchers with a combination of complementary expertise to examine peptidic KOR ligands for potential treatment of cocaine abuse. The specific aims of the research are:1) to design and synthesize peptidic KOR ligands, both agonists and antagonists, with improved blood-brain barrier penetration and pharmacokinetic parameters, including metabolic stability; 2) to evaluate peptide ligands in vitro for opioid receptor affinity and efficacy, potential non-opioid receptor mediated neurotoxicity, blood brain barrier transport, metabolism and pharmacokinetic properties; and 3) to evaluate selected peptide ligands in vivo, initially for opioid activity and duration of action in pain models, followed by examination in models of cocaine abuse. We expect that we will identify peptide KOR ligands that can be administered systemically to therapeutically prevent cocaine-seeking behavior.

描述（由申请人提供）：滥用毒品是个人和社会后果的一个严重问题，可卡因是一种主要的非法滥用药物，尽管如此，美国仍有近200万可卡因使用者在美国，目前尚无药物治疗可卡因滥用和成瘾，迫切需要检查毒品对滥用Cocaine的治疗的药物。众所周知，可卡因可以部分通过阻止终止多巴胺信号传导的多巴胺转运蛋白来发挥作用，从而增强了多巴胺信号传导，这被认为与该药物的奖励作用有关。值得注意的是，Kappa阿片受体（KO）的激活抑制了多巴胺信号，因此可能抵消可卡因的作用。有广泛的证据表明，Kor激动剂可以急性抑制可卡因的奖励和自我管理。这里的初步证据表明，一种新型的肽kor激动剂通过急性刺激Kor抑制了可卡因的奖励。尽管这证明了急性Kor激动剂在治疗可卡因滥用方面的治疗价值，但反复使用Kor激动剂的反复治疗可与可卡因的奖励作用增加。同样，暴露于压力是恢复药物寻求行为的关键因素，这种作用可能是由内源性KOR激动剂驱动器激活的kor系统介导的。我们假设肽kor拮抗剂可能会防止应力引起的恢复。在这里支持这一点的初步结果表明，与新型肽KOR拮抗剂进行预处理防止了压力引起的可卡因条件条件的位置偏好的恢复，这表明Kor拮抗剂可以作为有效的维持治疗，以防止对可卡因滥用的复发。该提案将一个高度协同的研究人员团队汇集在一起，具有互补专业知识的结合，以检查肽kor配体，以便对可卡因滥用的潜在治疗。研究的具体目的是：1）设计和合成肽kor配体，包括激动剂和拮抗剂，具有改善的血脑屏障渗透和药代动力学参数，包括代谢稳定性； 2）在体外评估肽配体的阿片受体亲和力和功效，潜在的非阿片受体介导的神经毒性，血液脑屏障的转运，代谢和药代动力学特性； 3）在体内评估选定的肽配体，最初是用于阿片类药物活性和疼痛模型中的作用持续时间，然后在可卡因滥用模型中检查。我们预计我们将确定可以系统地管理的肽kor配体，以防止可卡因寻求可卡因的行为。