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，慢性复发的临床病症，对个人和公共卫生都有严重后果。可卡因是一种主要的非法滥用药物，在美国有超过500万的可卡因使用者，但目前还没有批准用于治疗可卡因滥用和成瘾的药物。因此，迫切需要研究和开发新的医疗实体（NME）作为治疗可卡因滥用和成瘾的疗法。可卡因增强了多巴胺的信号，多巴胺是一种神经递质，与这种药物的有益作用有关。Kappa阿片受体（KOR）及其内源性肽激动剂dynorphins显著调节多巴胺能功能。此外，dynorphin信号与应激反应有关，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拮抗剂可以防止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防止可卡因滥用的复发。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），这可能使其治疗发展复杂化。因此，具有更有限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，它可以选择性地在有限的时间内（小时）拮抗KOR，并防止口服给药后应激诱导的消失的可卡因寻求行为的恢复。这种环肽是开发治疗可卡因成瘾和可卡因滥用复发药物的重要先导化合物。该提案汇集了一组具有高度协同专业知识的研究人员，从类似物的设计和合成到临床前模型中作为可卡因成瘾潜在治疗方法的评估，以推进这种新型环铅肽的开发。拟建的研究包括四个具体目标：1)环铅肽类似物的合成，并通过初步体外实验验证其对KOR的亲和力、选择性、拮抗剂活性和无神经毒性；2)通过激动剂诱导的啮齿动物抗疼痛实验进行体内初步药理学评价，以确定新型肽的KOR拮抗剂活性，并分析其体外药代动力学特性；3)在啮齿类动物奖励模型（条件位置偏好和自我给药试验）中评估预防已消失的可卡因寻求行为恢复的治疗效果，同时测试可能出现的不良身体和行为影响，并进行体内药代动力学分析；4)在非人类灵长类动物中进行优化候选药物的药效学和药代动力学分析，作为支持潜在的后期基于调控的研究的关键转化步骤。这项研究有望产生候选药物，可以合理和有效地推进到后期临床前开发，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.