Investigation of Neoclerodanes as Novel Opioid Ligands

 描述(由申请人提供)：对可卡因和甲基苯丙胺的上瘾是高度上瘾的精神刺激剂，与大量神经精神疾病的共同发病有关，还会增加艾滋病毒-1、乙肝和丙型肝炎的传播，从而造成巨大的公共卫生成本。目前还没有FDA批准的治疗精神刺激性成瘾的方法。越来越多的证据表明，κ阿片(KOP)受体(及其内源性高效激动剂神经肽强啡肽)参与了精神刺激剂的主要滥用相关效应的调节，尤其是复发。植物来源的迷幻剂Salvinorin A是一种结构独特的KOP激动剂，它来自丹参薄荷。参比Kop-r激动剂和Salvinorin A可以减少某些精神刺激剂诱导的效应，但这些理想的作用伴随着不良的影响，包括前述的幻觉、镇静和烦躁/厌恶。从本项目前期选择的新型半合成新甾烷具有作为精神刺激性成瘾的“先导”药物治疗剂的潜力，如它们在体外和体内翻译模型中的分布所示， 包括减少不良行为影响的负担。这一提议的中心假设是，这些新的克罗烷“先导”的迭代结构修饰将产生新的阿片受体配体，有可能治疗精神刺激性成瘾、复发和共病的神经精神障碍。这项建议的具体目标是：(1)优化新型新核桃烷的活性，包括创新的合成反式十氢萘类似物，在KOP受体上的活性；(2)确定和优化新型新核盘烷作为KOPr配体在小鼠体内的活性，以及它们减少可卡因诱导效应的能力；以及(3)在翻译的非人类灵长类动物模型中，确定和优化从目标1和2优先考虑的新型新核盘烷的活性。这项拟议的研究具有创新性，因为新甾烷是一类独特的阿片受体配体。这些分子的设计、合成和评估将对开发与阿片受体相互作用的新药物探针产生广泛影响。这些信息有望有助于确定临床上有用的KOP-r靶向药物来治疗药物成瘾。

 DESCRIPTION (provided by applicant): Addiction to cocaine and methamphetamine, highly addictive psychostimulants, is associated with substantial neuropsychiatric co-morbidity, and also enhances transmission of HIV-1, hepatitis B and C and thus causes massive public health costs. There are currently no FDA-approved treatments for psychostimulant addiction. Growing evidence shows that that κ opioid (KOP) receptors (and their endogenous high-efficacy agonist neuropeptides, the dynorphins) are involved in the modulation of major abuse-related effects of psychostimulants, and particularly relapse. The plant-derived hallucinogen, salvinorin A (a neoclerodane), from the mint Salvia divinorum, is a structurally unique KOP-agonist. Reference KOP-r agonists and salvinorin A can decrease certain psychostimulant-induced effects, but these desirable actions are accompanied by undesirable effects, including the aforementioned hallucinations, sedation and dysphoria/aversion. Selected novel semi-synthetic neoclerodanes from the previous period of this Project have potential as "lead" pharmacotherapeutic agents for psychostimulant addiction, as shown by their in vitro and in vivo profiles in translational models, including a reduced burden of undesirable behavioral effects. The central hypothesis of this proposal is that iterative structural modification of these neoclerodane "leads" will generate novel opioid receptor ligands with the potential to treat psychostimulant addiction, relapse, and co-morbid neuropsychiatric disorders. The Specific Aims of this proposal are (1) optimize the activity of novel neoclerodanes, including innovative synthetic trans-decalin analogs, at KOP receptors; (2) determine and optimize the in vivo activity of novel neoclerodanes as KOPr ligands in mice, and for their ability to decrease cocaine-induced effects; and (3) determine and optimize the activity of novel neoclerodanes prioritized from Aims 1 and 2, in translational non- human primate models. The proposed research is innovative because neoclerodanes are a unique class of opioid receptor ligands. The design, synthesis, evaluation of these molecules will have a broad impact on development of new pharmacologic probes that are designed to interact with opioid receptors. This information is expected to facilitate the identification of clinically useful KOP-r targeted medications for the treatment of drug addiction.