OPIOIDS WITH DELTA ANTAGONIST AND MU AGONIST ACTIVITY

慢性临床疼痛仍然没有得到很好的治疗。使用Mu阿片类止痛剂，如吗啡，可以治疗疼痛，但吗啡和其他Mu激动剂的严重不良影响限制了它们的使用。事实上，耐受性的快速发展导致给药剂量不断增加，增加了不良影响的严重性。最近的研究表明，与单独使用吗啡相比，增量阿片拮抗剂与吗啡联合使用会导致耐受性的建立较慢。此外，据报道，使用具有MU激动剂/德尔塔拮抗剂双重特性的多肽引起的耐受性很小。因此，目前研究的目的是开发有效的非肽Mu激动剂，它也具有Delta拮抗作用。奥维诺(如依托啡)是一类有效的MU阿片激动剂，也与Kappa和Delta受体相互作用，通常表现为Delta激动剂。我们的假设是，在吲哚吗啉(例如，纳曲酮、氧吗啡)中的吲哚或类阿片亚甲基(例如，亚苄基)中的亚苄基的位置上引入一个芳基，可以降低奥维诺的增量效应。通过降低增量药效、降低卡帕亲和力和保持高的单位药效，将产生具有所需轮廓的冰片脑醇的类似物。所使用的方法包括使用新的分子建模方法开发Delta拮抗的药效团模型，以及选择具有适当位置的芳环的目标分子。这一新的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来进行测试。从简单的吗啡类化合物中获得的信息将被用于设计和合成模型所选择的目标5，14-桥联吗啡类化合物。新的化学方法将被开发并应用于6，14-桥联目标的合成，这些类似物与冰片醇关系非常密切。这项建议的最终目标是开发有效的MU阿片类止痛药，对其产生耐受性缓慢或根本不产生，以减少临床疼痛的慢性治疗中出现的不良影响。

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.