Development of Novel Opioid Peptides for Cocaine Abuse

描述(申请人提供)：药物滥用/成瘾是一种严重的、长期复发的临床症状，对个人和公共健康都有严重的后果。可卡因是一种主要的非法滥用药物，美国有500多万可卡因使用者，但目前还没有被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传递，多巴胺是一种与这种药物的回报作用相关的神经递质。Kappa阿片受体(KOR)及其内源性多肽激动剂强啡肽显著调节多巴胺能功能。此外，强啡肽信号参与了对压力的反应，这是恢复已消失的寻求药物行为的关键因素。选择性KOR拮抗剂可以在动物实验中防止应激诱导的可卡因寻找行为的恢复，因此有可能作为维持药物来防止再次滥用可卡因。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)，这可能会使它们的治疗发展复杂化。因此，新的选择性KOR拮抗剂具有更有限的作用时间，可能是进一步开发为潜在治疗药物的重要先导化合物。我们已经确定了一种新的小环肽，它选择性地在有限的持续时间(小时)内拮抗KOR，并防止口服给药后应激诱导的消失的可卡因寻找行为的恢复。这种环肽是开发治疗可卡因成瘾和复吸可卡因滥用药物的重要先导化合物。这项提议汇集了一组具有高度协同专业知识的研究人员，以推动这种新型先导环肽的开发，从设计和合成类似物到他们在临床前模型中作为潜在的可卡因成瘾治疗方法的评估。这项研究涉及四个具体目标：1)合成铅环肽类似物，并在体外初步验证它们的KOR亲和力、选择性、拮抗剂活性和无神经毒性；2)在激动剂诱导的啮齿动物抗伤害作用试验中进行体内初步药理学评价，以确定新多肽的KOR拮抗剂活性，并在体外分析其药代动力学特性；3)在啮齿动物模型中评价奖赏(条件性位置偏爱和自我给药试验)防止戒除的可卡因寻找行为复发的疗效，并进行可能的不良躯体和行为影响的试验，以及体内药代动力学分析；以及4)对非人类灵长类动物的优化候选进行药效学和药代动力学分析，作为支持潜在的基于调控的研究的关键转换步骤。这项研究有望产生能够合理和有效地推进到晚期临床前开发的候选药物，作为治疗可卡因成瘾和复发的潜在疗法。 公共卫生相关性：kappa阿片受体(KOR)拮抗剂有可能成为治疗可卡因成瘾和复发的维持药物，但小分子KOR拮抗剂的开发因其异常长的药理活性而受到阻碍。一种新的小肽KOR拮抗剂在初步研究中被证明可以防止口服给药后应激诱导的寻找可卡因行为的复发。这项建议侧重于优化这种多肽的药代动力学和药效学特性，以产生潜在的可卡因成瘾和复发治疗候选药物。

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. PUBLIC HEALTH RELEVANCE: Antagonists of kappa opioid receptors (KOR) have potential as maintenance medications to treat cocaine addiction and relapse, but the development of small molecule KOR antagonists has been hampered by their unusually prolonged pharmacological activity. A novel small peptide KOR antagonist was shown in preliminary studies to prevent stress-induced relapse of cocaine-seeking behavior after oral administration in rodents. This proposal focuses on optimizing the pharmacokinetic and pharmacodynamic properties of this peptide in order to generate candidates for development as potential treatments for cocaine addiction and relapse.