Development of Novel Opioid Peptides for Cocaine Abuse

描述（由申请人提供）：药物滥用/成瘾是一种严重的、慢性复发性临床疾病，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，在美国有超过500万可卡因使用者，然而，目前还没有批准用于治疗可卡因滥用和成瘾的药物。因此，迫切需要研究和开发新的医学实体（NME）作为治疗可卡因滥用和成瘾的治疗剂。可卡因增强多巴胺的信号传导，多巴胺是一种与这种药物的奖励作用有关的神经递质。κ阿片受体（KOR）及其内源性肽激动剂强啡肽显著调节多巴胺能功能。此外，强啡肽信号转导与应激反应有关，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拮抗剂可以预防应激诱导的可卡因寻求行为的恢复，因此有可能作为维持药物来预防可卡因滥用的复发。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（即单次给药后数周），这可能使其治疗开发复杂化。因此，具有更有限的作用持续时间的新型选择性KOR拮抗剂可能是作为潜在治疗剂进一步开发的重要先导化合物。我们已经确定了一种新的小环肽，选择性拮抗KOR有限的持续时间（小时），并防止口服给药后，消除可卡因寻求行为的应激诱导的恢复。该环肽代表了用于开发用于治疗可卡因成瘾和可卡因滥用复发的药剂的重要先导化合物。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其在临床前模型中作为可卡因成瘾的潜在治疗方法的评估。本研究的主要目的是：1）合成先导环肽的类似物，并在体外初步验证其对KOR的亲和力、选择性、拮抗活性和无神经毒性; 2）在啮齿类动物中通过激动剂诱导的抗伤害感受试验进行初步的体内药理学评价，以确定新肽的KOR拮抗活性，并分析其体外药代动力学性质; 3）在啮齿动物奖励模型中的体内评价（条件性位置偏爱和自我给药测定），用于预防已消失的可卡因寻求行为的恢复的治疗功效，同时测试可能的不良躯体和行为效应，以及体内药代动力学分析;和4）优化的候选物在非人灵长类动物中的药效学和药代动力学分析，作为支持潜在的后续监管研究的关键转化步骤。这项研究有望产生候选药物，这些药物可以合理和有效地进入后期临床前开发，作为可卡因成瘾和复发的潜在治疗方法。

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.