Peptidic Kappa Opioid Receptor Ligands as Potential Treatments for Drug Addiction

描述（由申请人提供）：药物滥用是一个严重的问题，对个人和社会都有影响，可卡因是一种主要的非法药物滥用，在美国有近200万可卡因使用者，尽管如此，目前还没有药物可用于治疗可卡因滥用和成瘾，突出表明迫切需要检查药物治疗可卡因滥用的治疗潜力。众所周知，可卡因的作用部分是通过阻断负责终止多巴胺信号的多巴胺转运体，从而增强多巴胺信号，而多巴胺信号被认为与这种药物的有益作用有关。值得注意的是，kappa阿片受体（KOR）的激活会抑制多巴胺信号，从而可能抵消可卡因的作用。有大量证据表明，KOR激动剂可以急性抑制可卡因奖励和自我给药。这里的初步证据表明，一种新的肽KOR激动剂通过急性刺激KOR抑制可卡因奖励。虽然这证明了急性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激动剂治疗却自相矛盾地显示出可卡因的奖励效应增加。同样，暴露于压力是恢复药物寻求行为的关键因素，这种影响可能是由内源性KOR激动剂dynorphin激活KOR系统介导的。我们假设肽KOR拮抗剂可能因此阻止应激诱导的恢复。为了支持这一观点，本研究的初步结果表明，使用新型肽KOR拮抗剂预处理可以防止应激诱导的可卡因条件位置偏好的恢复，这表明KOR拮抗剂可以作为有效的维持治疗来防止可卡因滥用的复发。该提案汇集了一个高度协同的研究团队，并结合了互补的专业知识，以检查肽性KOR配体对可卡因滥用的潜在治疗。本研究的具体目的是：1)设计和合成肽型KOR配体，包括激动剂和拮抗剂，具有更好的血脑屏障穿透性和药代动力学参数，包括代谢稳定性；2)评价肽配体在体外对阿片受体的亲和力和有效性、潜在的非阿片受体介导的神经毒性、血脑屏障转运、代谢和药代动力学特性的影响；3)在体内评估选定的肽配体，首先在疼痛模型中评估阿片活性和作用持续时间，然后在可卡因滥用模型中进行检查。我们期望我们将确定肽KOR配体，可以系统地给予治疗，以防止可卡因寻求行为。

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.