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

• 批准号: 8857378
• 负责人: Jane V Aldrich
• 金额: $ 61.54万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8857378
• 关键词: Abstinence; Advanced Development; Adverse effects; Affect; Affinity; Agonist; Animal Model; Behavior; Biological Assay; Biological Factors; Brain; Chronic; Cocaine; Cocaine Abuse; Cocaine Dependence; Cocaine Users; Cues; D-Phe-Pro; Data; Development; Disease; Dopamine; Drug Addiction; Drug Exposure; Drug Kinetics; Dynorphin A; Dynorphins; Equilibrium; Evaluation; Exhibits; Exposure to; FDA approved; Goals; Grant; Health; Illicit Drugs; In Vitro; Individual; Interdisciplinary Study; Investigation; Isomerism; Laboratories; Lead; Ligands; Liver Microsomes; Maintenance; Mediating; Metabolism; Modeling; Mus; Opioid; Opioid Peptide; Opioid Receptor; Oral; Oral Administration; Pathway interactions; Peptides; Permeability; Pharmaceutical Preparations; Plasma Proteins; Property; Protein Binding; Proteins; Public Health; Qualifying; Relapse; Reporting; Research; Research Personnel; Rewards; Sedation procedure; Self Administration; Signal Transduction; Smooth Muscle; Societies; Staging; Stress; Structure; Structure-Activity Relationship; System; Testing; Therapeutic; Translational Research; analog; cocaine exposure; cocaine relapse prevention; design; disorder later incidence prevention; dopamine transporter; drug of abuse; drug seeking behavior; endogenous opioids; extracellular; improved; in vivo; interdisciplinary approach; monolayer; mu opioid receptors; novel; phenylalanyltryptophan; pre-clinical; preference; prevent; programs; research study; therapeutic development

DESCRIPTION (provided by applicant): Cocaine abuse is a serious relapsing condition that affects both individuals and public health. While cocaine is a major illegal drug of abuse, with almost 5 million cocaine users in the US, there are currently no medications approved for the treatment of cocaine abuse and addiction. Relapse to drug seeking behavior after a period of abstinence is a major challenge in the long term treatment of cocaine abuse, with both stress and exposure to cocaine contributing to relapse. Thus there is a pressing need to identify and develop new compounds as potential therapeutics for the prevention of relapse to cocaine abuse. The kappa opioid receptor (KOR) system modulates dopaminergic pathway function, and ligands for KOR have demonstrated potential as therapeutics for cocaine abuse. KOR agonists have been shown to prevent cocaine-seeking behavior and cocaine-primed relapse of drug-seeking behavior following abstinence. Additionally, KOR selective antagonists can prevent stress-induced reinstatement of cocaine-seeking behavior that is mediated by the release of endogenous KOR agonists and activation of KOR. However, until recently, no single opioid ligand had been reported that is capable of preventing both of these important triggers for reinstatement of drug seeking behavior. This competitive renewal focuses on optimizing the structure of a novel mixed opioid agonist/KOR antagonist ligand that we have demonstrated can prevent both cocaine- and stress-induced reinstatement of cocaine-seeking behavior after oral administration. Recent studies with this lead compound demonstrate the importance of its balanced opioid activity in the minimization of potential side effects such as sedation and conditioned place preference or aversion. Additional studies indicate it exerts its effects on the opioid system in vivo through a novel combination of both direct and indirect mechanisms. Our optimization efforts will focus on improving the pharmacokinetic properties of the lead compound to enhance its oral activity while retaining its balanced opioid agonist/KOR antagonist profile. The proposed multidisciplinary research will be performed by a highly qualified team of researchers with synergistic expertise, and consists of three specific aims: 1) synthesis of analogs of the lead compound to enhance its oral activity, 2) in vitro pharmacological and pharmacokinetic studies of the analogs to optimize these important parameters, and 3) evaluation of the compounds in vivo for their opioid receptor profile and their ability to prevent cocaine-seeking behavior. This translational research program is expected to produce optimized analogs that can be advanced into the later stages of preclinical development as potential treatments for cocaine addiction and relapse.

描述（由申请人提供）：可卡因滥用是一种严重的复发状况，影响个人和公共卫生。尽管可卡因是一种主要的非法滥用药物，但在美国有近500万可卡因使用者，但目前尚无批准用于治疗可卡因滥用和成瘾的药物。一段时间的禁欲后，人们对毒品寻求行为的复发是长期治疗可卡因滥用的主要挑战，既压力和暴露于可卡因，都有促进复发。因此，迫切需要识别和开发新化合物，作为预防可卡因滥用复发的潜在治疗剂。 Kappa阿片受体（KOR）系统调节多巴胺能途径功能，而KOR配体具有作为可卡因滥用的治疗方法的潜力。已证明KOR激动剂可以防止可卡因寻求可卡因的行为和禁欲后吸毒行为的可卡因复发。此外，KOR选择性拮抗剂可以防止应力引起的可卡因寻求行为的恢复，而可卡因寻求行为是由内源性Kor激动剂释放和KOR激活介导的。但是，直到最近，还没有据报道单一的阿片类药物配体能够防止这两种重要的触发器恢复毒品寻求行为。 这种有竞争力的更新着重于优化我们已证明的新型混合阿片类药物/kor拮抗剂配体的结构，可以防止可卡因和压力诱导的口服后恢复可卡因寻求可卡因行为。该铅化合物的最新研究表明，其平衡的阿片类药物活性在最小化潜在副作用（例如镇静和条件的位置偏好或厌恶）中的重要性。其他研究表明，它通过直接和间接机制的新型组合对体内阿片类药物系统产生影响。我们的优化工作将着重于提高铅化合物的药代动力学特性，以增强其口腔活性，同时保留其平衡的阿片类动力学/Kor拮抗剂。 The proposed multidisciplinary research will be performed by a highly qualified team of researchers with synergistic expertise, and consists of three specific aims: 1) synthesis of analogs of the lead compound to enhance its oral activity, 2) in vitro pharmacological and pharmacokinetic studies of the analogs to optimize these important parameters, and 3) evaluation of the compounds in vivo for their opioid receptor profile and their ability to prevent寻求可卡因的行为。预计该翻译研究计划将产生优化的类似物，这些类似物可以作为可卡因成瘾和复发的潜在处理临床前发展阶段。