Opiods with Delta Antagonist and Mu Agonist Activity

描述(由申请人提供)：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。研究表明，与单独使用吗啡相比，增量阿片拮抗剂与吗啡共同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，这一持续研究项目的目的是开发有效的非肽MU激动剂，它也具有三角洲拮抗作用。 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，一般表现为Delta激动剂。我们的假设是，在两类重要的低效增量阿片配体--吲哚类化合物(例如，纳曲诺)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，可以降低奥维诺类化合物的增量效应。通过降低增量效率并保持较高的单位效率，将产生具有所需轮廓的奥维诺的类似物。 将使用的方法包括使用新的分子建模方法开发Delta有效性的药效团模型，以及设计具有适当位置的芳环的目标分子。包括由模型选择的5，14-桥联和6，14-桥联吗啡基的冰片酚。新的化学方法将被开发并应用于6，14-桥联-4，5-环氧吗啡烷目标的合成，这些类似物与冬凌草醇类化合物关系密切。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。

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.