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

Salvinorin A立体异构体和去甲基类似物的SAR的建立

• 批准号: 8636424
• 负责人: Judd Berman
• 金额: $ 10.58万
• 依托单位: DALTON MEDICINAL CHEMISTRY, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2015-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8636424
• 关键词: Address; Affinity; Agonist; Binding; Biological Assay; Cocaine Dependence; Diterpenes; Human Cloning; Knowledge; Ligands; Manic; Mental Depression; Mono-S; Opioid Receptor; Pain; Research; Salvia; Stereoisomer; Substance abuse problem; Testing; Therapeutic Agents; analog; mu opioid receptors; neoclerodane; novel; novel therapeutics; public health relevance; receptor; salvinorin A; scaffold; stereochemistry

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.

性状（由申请方提供）：鼠尾草的活性成分是鼠尾草素A，一种新克罗烷二萜类化合物，是一种强效和选择性κ阿片受体激动剂。它是唯一已知的不含氮的阿片受体配体，具有与κ-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κ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，κ-阿片受体选择性拮抗剂代表了可卡因成瘾、抑郁症和躁狂症的潜在治疗。因此，鼠尾草素A代表了一个非常有趣的起点，以解决这两个紧迫的问题，以及获得有关κ阿片受体的重要结构信息。为了解决这些挑战，我们建议完成鼠尾草素A立体化学对其激动剂/部分激动剂/拮抗剂特征影响的SAR。迄今为止，已经探索了鼠尾草素A的七个立体中心中的三个对k阿片受体的亲和力和效力的影响。直接目标是建立鼠尾草素A的剩余立体中心的SAR，以便可以鉴定新的合成κ-阿片受体选择性激动剂/部分激动剂/拮抗剂谱支架，并为CNS阿片受体提供新的探针。这项研究的长期目标是使用该提案中确定的支架作为发现新治疗药物的起点，以治疗疼痛和药物滥用。具体目标#1：合成鼠尾草素A的四种立体异构体和合成鼠尾草素A的三种脱甲基（C5、C9单脱甲基和二脱甲基）类似物。具体目标#2：测试每种立体异构体与三种克隆的人阿片受体（μ、δ和κ）结合的选择性，并在功能测定中确定其激动剂/拮抗剂特征。这项研究将补充目前对鼠尾草素A的SAR知识，并对我们理解κ-阿片受体的立体化学要求做出重大贡献。