Establishment of the SAR of Salvinorin A stereoisomers and des-Methyl Analogs

说明(申请人提供)：丹参的活性成分是丹参甲素，是一种有效的选择性kappa-阿片受体激动剂。它是已知的唯一一种非含氮阿片受体配体，具有与kappa-阿片受体蛋白结合的独特模式。越来越多的证据表明，非肽类kappa-阿片受体选择性激动剂可能是一种潜在的疼痛治疗方法。此外，kappa-阿片受体选择性拮抗剂代表着治疗可卡因成瘾、抑郁和躁狂的潜在方法。因此，萨尔维诺林A是解决这两个紧迫问题以及获得关于kappa-阿片受体的重要结构信息的一个特别耐人寻味的起点。为了应对这些挑战，我们建议完成Salvinorin A的立体化学对其激动剂/部分激动剂/拮抗剂图谱的影响的SAR。到目前为止，关于Salvinorin A的七个立体产生中心中的三个对k阿片受体的亲和力和效力的影响已经被探索过。近期的目标是建立Salvinorin A的剩余立体中枢的SAR，以便能够识别新的合成kappa-阿片受体选择性激动剂/部分激动剂/拮抗剂轮廓支架，并为中枢阿片受体提供新的探针。这项研究的长期目标是使用本提案中确定的支架作为发现治疗疼痛和药物滥用的新治疗剂的起点。为了探索这一主题，我们将追求这两个特定目标：特定目标#1：合成四个Salvinorin A的立体异构体和合成三个Salvinorin A的去甲基(C5、C9单甲基和二Des-甲基)类似物。特定目标#2：测试每个立体异构体与三个克隆的人类阿片受体(u、Delta和kappa)结合的选择性，并在功能分析中确定它们的激动剂/拮抗剂图谱。这项研究将补充目前对丹参素A的SAR知识，并对我们理解kappa-阿片受体的立体化学要求做出重大贡献。

DESCRIPTION (provided by applicant): The active component of Salvia Divinorum is Salvinorin A a neoclerodane diterpenoid which is a potent and selective kappa-opioid receptor agonist. It is the only known non-nitrogen containing opioid receptor ligand with a unique mode of binding to the kappa-opioid receptor protein. There is growing evidence to suggest that nonpeptidic kappa-opioid receptor selective agonists could be a potential treatment for pain. Additionally, kappa-opioid receptor selective antagonists represent a potential treatment for cocaine addiction, depression and mania. Thus, Salvinorin A represents an exceptionally intriguing starting point to address these two pressing issues as well as to gain important structural information about the kappa-opioid receptor. To address these challenges we propose to complete the SAR of the effects of the stereochemistry of Salvinorin A on its agonist/partial agonist/ antagonist profile. The effects of three of the seven stereogenic centers of Salvinorin A with respect to affinity and potency at the k opioid receptor have been explored to date. The immediate objective is to establish the SAR of the remaining stereocenters of salvinorin A so that new synthetic kappa-opioid receptor selective agonist/partial agonist/antagonist profile scaffolds can be identified and provide novel probes for CNS opioid receptors. The long-term objective of this research is to use the scaffolds identified in this proposal as the starting poins for the discovery of new therapeutic agents to treat pain and substance abuse. To explore this theme we will pursue these two specific aims: Specific Aim #1: Synthesis of four stereoisomers of Salvinorin A and synthesis of three des-methyl (C5, C9 mono-des-methyl and di-des-methyl) analogs of Salvinorin A. Specific Aim #2: Test each of the stereoisomers for selectivity of binding to the three cloned human opioid receptors (mu, delta and kappa) and determine their agonist/antagonist profile in a functional assay. This study will compliment the current SAR knowledge of Salvinorin A and make a significant contribution to our understanding of the stereochemical requirements of the kappa-opioid receptor.