Peptidic Kappa Opioid Receptor Ligands as Potential Treatments for Drug Addiction

描述（由申请人提供）：可卡因滥用是一种严重的复发性疾病，影响个人和公众健康。虽然可卡因是一种主要的非法滥用药物，在美国有近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。戒毒一段时间后重新出现寻求药物的行为是长期治疗可卡因滥用的一个主要挑战，压力和暴露于可卡因都会导致复发。因此，迫切需要鉴定和开发新的化合物作为预防可卡因滥用复发的潜在治疗剂。 κ阿片受体（KOR）系统调节多巴胺能通路功能，并且KOR的配体已被证明具有作为可卡因滥用的治疗剂的潜力。KOR激动剂已被证明可以预防可卡因成瘾行为和戒断后可卡因引发的吸毒行为复发。此外，KOR选择性拮抗剂可以防止由内源性KOR激动剂的释放和KOR的激活介导的可卡因寻求行为的应激诱导的恢复。然而，直到最近，还没有单一的阿片类配体被报道能够阻止这两个重要的触发恢复药物寻求行为。 这种竞争性更新的重点是优化一种新型混合阿片类激动剂/KOR拮抗剂配体的结构，我们已经证明这种配体可以预防口服给药后可卡因和应激诱导的可卡因寻求行为的恢复。最近对这种先导化合物的研究表明，其平衡的阿片活性在最大限度地减少潜在副作用（如镇静和条件性位置偏爱或厌恶）方面的重要性。其他研究表明，它通过直接和间接机制的新组合对体内阿片系统发挥作用。我们的优化工作将集中在改善先导化合物的药代动力学特性，以增强其口服活性，同时保持其平衡的阿片类激动剂/KOR拮抗剂特征。拟议的多学科研究将由具有协同专长的高素质研究人员团队进行，包括三个具体目标：1）合成先导化合物的类似物以增强其口服活性，2）类似物的体外药理学和药代动力学研究以优化这些重要参数，和3）在体内评价化合物的阿片样物质受体分布和它们防止可卡因寻求行为的能力。这项转化研究计划预计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治疗方法进入临床前开发的后期阶段。

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.