OPIOIDS WITH DELTA ANTAGONIST AND MU AGONIST ACTIVITY

慢性临床疼痛仍然治疗不力。 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。 最近的工作表明，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，目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。奥维醇（例如埃托啡）是一类也与κ和δ受体相互作用的有效μ阿片样物质激动剂，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、羟吗啡吲哚）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、降低κ亲和力和保持高μ功效，将产生具有所需特征的奥维醇类似物。所使用的方法包括使用新的分子建模方法开发δ拮抗作用的药效团模型，以及选择具有适当定位的芳环的靶分子。 新的模型将通过合成简单的吗啡喃含有满足药效团的芳香族化合物进行测试。 从简单的吗啡喃中获得的信息将被应用于设计和合成由模型选择的目标5，14-桥连吗啡喃基orvinols。 新的化学方法将被开发和应用于合成6，14-桥接的目标，类似物非常密切相关的orvinols。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。

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.