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: 8013890
• 负责人: ANDREW COOP
• 金额: $ 29.5万
• 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/8013890
• 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 Receptor; Oxymorphone; Pain; Peptides; Positioning Attribute; Principal Investigator; Reporting; Research Project Grants; Rice; Severities; analog; base; delta opioid receptor; design; kappa opioid receptors; 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）：慢性临床疼痛的治疗效果仍然不佳。使用吗啡等 mu 阿片类镇痛药可以治疗疼痛，但吗啡和其他 mu 激动剂的严重不良反应限制了其使用。事实上，耐受性的快速发展导致给药剂量不断增加，从而增加了不良反应的严重性。研究表明，与单独使用吗啡相比，同时使用 δ 阿片拮抗剂和吗啡会导致耐受性的建立更慢。此外，据报道，使用具有μ激动/δ拮抗双重特性的肽几乎不会产生耐受性。因此，这个持续研究项目的目的是开发有效的非肽 mu 激动剂，它也具有 δ 拮抗作用。 奥维诺（例如埃托啡）是一类有效的 mu 阿片类激动剂，也与 κ 和 δ 受体相互作用，通常表现出 δ 激动作用。我们的假设是，通过在吲哚吗啡喃（例如纳曲吲哚）中吲哚的位置或阿片类亚苄基中亚苄基（例如亚苄基纳曲酮（BNTX） ))，两类重要的低效δ阿片配体。通过降低 delta 功效并保留高 mu 功效，将产生具有所需特性的 orvinol 类似物。 所使用的方法包括使用新颖的分子建模方法开发delta功效的药效团模型，以及设计具有适当位置的芳环的目标分子。包括模型选择的基于 5,14-桥联和 6,14-桥联吗啡喃的奥维诺。新的化学方法将被开发并应用于 6,14-桥接-4,5-环氧吗啡喃靶标的合成，该类似物与 orvinol 非常密切相关。该提案的最终目标是开发有效的μ阿片类镇痛药，其耐受性发展缓慢或根本不产生，以减少临床疼痛慢性治疗中出现的不良影响。