Novel Probes of the Kappa Opioid Receptor: Chemistry, Pharmacology, and Biology

描述（由申请人提供）：我们计划开发新的κ阿片受体（KOR）靶向药物用于治疗药物成瘾。我们的主要目标是确定拮抗剂和部分激动剂，因为它们可能是治疗成瘾和预防复发的最有希望的候选药物。KOR拮抗剂代表了一种可能在临床上有效改善多种类型药物滥用（包括可卡因、甲基苯丙胺、阿片类药物、酒精、大麻和尼古丁）治疗后恢复结果的靶标。虽然KOR拮抗剂确实存在，但它们具有不寻常的长效药理学特征（单次注射后数周），这可能最终掩盖其治疗潜力。目前，还没有批准的多药滥用治疗方法，因此，鉴于此类拮抗剂的前景，该提案已被提交给NIH项目公告：“多药成瘾治疗药物开发”（PAS：08-186）。在过去的3年里，我们一直与NIH赞助的分子库探针中心网络（MLPCN）合作，在KOR（1X 01 MH 084153 -01）鉴定新型探针和支架。在筛选了Sanford-Burnham化学基因组学中心的MLPCN化合物集合（300，000种结构多样的小分子化合物）后，发现了4种新的化学实体，它们在该受体上显示出有希望的选择性，效力和功效。此外，独立的化学工作确定了第五种化学支架，它也是独特的，并且对κ阿片受体具有高度选择性。该提案寻求5年的支持，以提供这些化合物的初步临床前表征和化学优化，使其成为候选药物。根据这一目标，我们将通过功能多样的基于细胞的试验充分表征化合物的药理学特性，目的是鉴定能够微调KOR反应性的化合物。将在小鼠模型中验证基于细胞的应答，评估抗伤害感受活性（用于基本确定化合物是否具有体内拮抗剂性质）以及其破坏应激诱导的可卡因条件性位置偏爱恢复的能力。将进行化合物的药物代谢和药代动力学研究，为后续药物化学优化轮次提供信息。我们热情的团队由成熟的药物和合成化学家以及阿片类药物神经药理学家（具有分子和行为药理学专业知识）组成。我们得到了一位GPCR药理学家的支持，他在高通量药物发现的行业水平检测开发方面拥有丰富的经验，同时也是药代动力学评估方面的专家。

DESCRIPTION (provided by applicant): We are proposing to develop new kappa opioid receptor (KOR) targeted drugs for the treatment of drug addiction. Our primary goal is to identify antagonists and partial agonists as these may be the most promising candidates for treating addiction to and preventing relapse. KOR antagonists represent a target that may be clinically efficacious for improving recovery outcomes following treatment for multiple types of drugs of abuse, including cocaine, methamphetamine, opiates, alcohol, cannabis and nicotine. While KOR antagonists do exists, they have unusually long acting pharmacological profiles (several weeks after single injection) which may ultimately obscure their therapeutic potential. Currently, there are no approved therapies for poly- drug abuse, therefore, given the promise of such antagonists, this proposal has been directed to the NIH program announcement: "Medications Development for Polydrug Addictions Treatment" (PAS: 08-186). Over the past 3 years, we have been working with the NIH-sponsored Molecular Libraries Probe Centers Network (MLPCN) to identify novel probes and scaffolds at the KOR (1X01MH084153-01). After screening the MLPCN compound collection at the Sanford-Burnham Center for Chemical Genomics (300,000 structurally diverse small molecule compounds), 4 novel chemical entities were discovered that display promising selectivity, potency and efficacy at this receptor. In addition, independent chemistry efforts identified a fifth chemical scaffold that is also unique, and highly selective of the kappa opioid receptor. This proposal seeks 5 years of support to provide the initial preclinical characterizations and chemical optimizations of these compounds into drug candidates. In line with this goal, we will fully characterize the pharmacological properties of the compounds across functionally diverse cell-based assays with of a goal of identifying compounds capable of fine-tuning KOR responsiveness. Cell-based responses will be validated in mouse models assessing antinociceptive activity (for basic determination if the compound has antagonist properties in vivo) as well as for its ability to disrupt stress-induced reinstatement of cocaine conditioned place preference. Drug metabolism and pharmacokinetics of the compounds will be performed to provide information for continued medicinal chemistry optimization rounds. Our enthusiastic team consists of established medicinal and synthetic chemists and an opioid neuropharmacologist (with both molecular and behavioral pharmacology expertise). We are supported by a GPCR pharmacologist with extensive experience in industry-level assay development for high throughput drug discovery as well as an expert in pharmacokinetic evaluations.