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: 6628359
• 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 2006-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6628359
• 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仍然不佳。 使用MU阿片类镇痛药（例如吗啡）可以治疗疼痛，但是吗啡和其他MU激动剂的严重不良影响限制了它们的使用。 实际上，耐受性的快速发展会导致不断增加的剂量，从而增加了不希望的影响的严重程度。 最近的工作表明，三角洲阿片类拮抗剂的共同给药，并且吗啡会导致耐受性较慢，而耐受性却慢于吗啡。 此外，据报道，使用具有MU激动剂/Delta拮抗的双重特征的肽的使用产生的耐受性很小。 因此，当前研究的目的是开发有效的非肽MU激动剂，这也具有Delta拮抗作用的特征。 Orvinols（例如伊托啡丁）是一类有效的MU阿片类动力学家，它们也与Kappa和Delta受体相互作用，通常显示出三角洲激动剂。 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三角洲阿片类药物配体。 通过降低三角洲疗效，降低KAPPA亲和力并保留高MU疗效，将会导致Orvinols的类似物具有所需的轮廓。使用的方法包括使用新型分子建模方法开发三角洲拮抗的药效团模型，以及选择具有适当定位的芳环的靶分子的选择。 新型模型将通过合成含有满足药理的芳香剂的简单形态来测试。 从简单的morphinans获得的信息将应用于该模型选择的基于5,14桥的基于Morphinan的Orvinols的设计和合成。 新型化学方法将开发并应用于6,14个桥梁靶标的合成，类似物与甲醇密切相关。该提案的最终目标是开发有效的MU阿片类镇痛药，耐受性会缓慢或根本不足，以减少慢性治疗临床疼痛的不良影响。