Investigation of Neoclerodanes as Novel Opioid Ligands

 描述（由申请方提供）：可卡因和甲基苯丙胺（高度成瘾性精神兴奋剂）成瘾与大量神经精神共病相关，也会增强HIV-1、乙型肝炎B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批准的治疗精神兴奋剂成瘾的方法。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）参与调节精神兴奋剂的主要滥用相关效应，特别是复发。植物源性致幻剂鼠尾草素A（一种新克罗烷），来自薄荷鼠尾草，是一种结构独特的KOP激动剂。参考KOP-r激动剂和鼠尾草素A可以降低某些精神兴奋剂诱导的作用，但这些期望的作用伴随着不期望的作用，包括上述幻觉、镇静和烦躁/厌恶。本项目前期选定的新型半合成新克罗烷具有作为精神兴奋剂成瘾的“主要”药理学药物的潜力，如其在转化模型中的体外和体内特征所示， 包括减少不希望的行为效应的负担。该提议的中心假设是，这些新克罗烷“先导物”的迭代结构修饰将产生新的阿片受体配体，其具有治疗精神兴奋剂成瘾、复发和共病神经精神障碍的潜力。该建议的具体目的是（1）优化新型新克罗烷（包括创新的合成反式-十氢化萘类似物）对KOP受体的活性;（2）确定和优化新型新克罗烷作为小鼠中的KOPr配体的体内活性，以及它们降低可卡因诱导作用的能力;和（3）在翻译的非人灵长类动物模型中，确定和优化根据目的1和2优先的新型新克罗烷的活性。拟议的研究是创新的，因为新氯烷是一类独特的阿片受体配体。这些分子的设计、合成和评价将对设计用于与阿片受体相互作用的新的药理学探针的开发产生广泛的影响。这一信息有望有助于识别临床上有用的KOP-r靶向药物，用于治疗药物成瘾。

 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.