Opiods with Delta Antagonist and Mu Agonist Activity

具有 Delta 拮抗剂和 Mu 激动剂活性的阿片类药物

• 批准号: 8101440
• 负责人: ANDREW COOP
• 金额: $ 2.4万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-02-01 至 2013-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101440
• 关键词: Agonist; Binding; Brain; Chemicals; Chronic; Clinical; Clinical Treatment; Development; Dose; Etorphine; Goals; Hydromorphone; Indoles; Ligands; Methodology; Modeling; Molecular Models; Morphinans; Morphine; Naloxone; Narcotic Antagonists; Opioid; Opioid Analgesics; Opioid Peptide; Opioid Receptor; Oxymorphone; Pain; Peptides; Positioning Attribute; Principal Investigator; Reporting; Research Project Grants; Rice; Severities; analog; base; delta opioid receptor; design; molecular modeling; mu opioid receptors; naltrindole; novel; pharmacophore; programs

DESCRIPTION (provided by applicant): Chronic clinical pain remains poorly treated. The use of mu opioid analgesics such as morphine can treat the pain, but the severe undesired effects of morphine and other mu agonists limit their use. Indeed, the rapid development of tolerance causes ever increasing doses to be administered, increasing the severity of the undesired effects. Studies have shown the coadministration of a delta opioid antagonist, together with morphine causes a slower build-up of tolerance than administration of morphine alone. Further, the use of a peptide with a dual profile of mu agonism/delta antagonism has been reported to give rise to little tolerance. Thus, the aim of this continuing research project is to develop potent non-peptide mu agonists, which also possess a profile of delta antagonism. The orvinols (e.g. etorphine) are a class of potent mu opioid agonists, that also interact with kappa and delta receptors, generally displaying delta agonism. Our hypothesis is that the delta efficacy of the orvinols can be reduced by the introduction of an aromatic group in a position that corresponds to the position of the indole in the indolomorphinans (e.g. naltrindole) or the benzylidene in the opioid benzylidenes (e.g. benzylidenenaltrexone (BNTX)), two important classes of low efficacy delta opioid ligands. By reducing delta efficacy and retaining high mu efficacy, analogs of the orvinols with the desired profile will result. The approach to be used consists of the development of a pharmacophore model of delta efficacy using a novel molecular modeling approach, and the design of target molecules with a suitably positioned aromatic ring. Included are 5,14-bridged and 6,14-bridged-morphinan based orvinols selected by the model. Novel chemical methodology will be developed and applied to the synthesis of 6,14-bridged-4,5-epoxymorphinan targets, analogs very closely related to the orvinols. The ultimate goal of this proposal is to develop potent mu opioid analgesics, to which tolerance develops slowly, or not at all, in order to reduce the undesired effects seen in the chronic treatment of clinical pain.

描述（由申请人提供）：慢性临床疼痛仍然治疗不良。使用μ阿片类镇痛药如吗啡可以治疗疼痛，但吗啡和其他μ激动剂的严重不良反应限制了它们的使用。事实上，耐受性的快速发展导致施用的剂量不断增加，增加了不期望的作用的严重性。研究表明，δ阿片拮抗剂与吗啡一起共同给药比单独给药吗啡引起更慢的耐受性建立。此外，据报道，使用具有μ激动/δ拮抗双重特征的肽几乎不产生耐受性。因此，该持续研究项目的目的是开发有效的非肽μ激动剂，其也具有δ拮抗作用。 奥维醇（例如埃托啡）是一类有效的μ阿片激动剂，其也与κ和δ受体相互作用，通常显示δ激动作用。我们的假设是，可以通过在与吲哚吗啡烷中的吲哚（例如纳曲吲哚）或阿片类苯亚甲基中的苯亚甲基（例如苯亚甲基萘酮（BNTX））的位置对应的位置引入芳族基团来降低奥维醇的δ功效，这两种重要类别的低功效δ阿片配体。通过降低δ功效并保持高μ功效，将产生具有所需特征的奥维醇类似物。 所使用的方法包括开发一个药效团模型的三角洲功效使用一种新的分子建模方法，并与一个适当定位的芳环的目标分子的设计。包括由模型选择的基于5，14-桥连和6，14-桥连吗啡喃的奥维醇。将开发新的化学方法并应用于合成6，14-桥连-4，5-环氧吗啡喃靶标，与orvinols非常密切相关的类似物。该提案的最终目标是开发有效的μ阿片类镇痛剂，对该镇痛剂的耐受性发展缓慢或根本不发展，以减少在临床疼痛的慢性治疗中观察到的不期望的作用。