OPIOIDS 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: 6845123
• 负责人: ANDREW COOP
• 金额: $ 22.28万
• 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 2008-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6845123
• 关键词: CHO cells; analgesics; analog; bridged cyclic compound; chemical models; chemical structure function; chronic pain; computer simulation; drug adverse effect; drug design /synthesis /production; drug screening /evaluation; drug tolerance; endogenous opioid; human genetic material tag; inhibitor /antagonist; laboratory mouse; ligands; molecular dynamics; molecular site; morphinans; opioid receptor; stimulant /agonist; tissue /cell culture

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. Recent work has 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 the current research 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, oxymorphindole) or the benzylidene in the opioid benzylidenes (e.g. benzylidenenaltrexone (BNTX)), two important classes of low efficacy delta opioid ligands. By reducing delta efficacy, decreasing kappa affinity, 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 antagonism using a novel molecular modeling approach, and the selection of target molecules with a suitably positioned aromatic ring. The novel model will be tested through the synthesis of simple morphinans containing aromatics that satisfy the pharmacophore. Information garnered from the simple morphinans will be applied to the design and synthesis of the target 5,14-bridged morphinan based orvinols selected by the model. Novel chemical methodology will be developed and applied to the synthesis of the 6,14-bridged 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.

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，耐受性的迅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程度。 最近的研究表明，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，当前研究的目的是开发有效的非肽μ激动剂，其也具有δ拮抗作用。奥维诺（例如埃托啡）是一类强效的 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、羟吗吲哚）中吲哚的位置或阿片类亚苄基（例如亚苄基纳曲酮）中亚苄基的位置对应的位置引入芳香族基团，可以降低奥维酚的δ功效。 (BNTX))，两类重要的低效 δ 阿片类配体。 通过降低 delta 功效、降低 kappa 亲和力并保留高 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δ拮抗药效团模型，以及选择具有适当位置的芳环的目标分子。 该新模型将通过合成含有满足药效团的芳香族化合物的简单吗啡喃来进行测试。 从简单吗啡喃获得的信息将应用于模型选择的目标 5,14-桥接吗啡喃基奥维诺的设计和合成。 新的化学方法将被开发并应用于 6,14-桥接靶标的合成，这些靶标与 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。