OPIOIDS WITH DELTA ANTAGONIST AND MU AGONIST ACTIVITY

慢性临床疼痛的治疗仍然很差。使用吗啡等阿片类镇痛药可以治疗疼痛，但吗啡和其他激动剂的严重不良反应限制了它们的使用。事实上，耐受性的迅速发展导致施用剂量不断增加，增加了不希望的影响的严重程度。最近的研究表明，与单独使用吗啡相比，三角洲阿片类拮抗剂与吗啡联合使用会导致耐受性的缓慢建立。此外，据报道，使用具有拮抗/拮抗双重特征的肽会产生很少的耐受性。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δ拮抗剂的特征。orvinols（例如etorphine）是一类有效的mu阿片受体激动剂，也与kappa和delta受体相互作用，通常表现为delta激动作用。我们的假设是，orvinol的δ效应可以通过在与吲哚在吲哚类（如纳曲多，氧吗啡吲哚）或苯基在阿片苯基中的位置相对应的位置上引入芳香基团而降低，苯基在阿片苯基中的位置（如苄基烯醛曲酮（BNTX）），这是两类重要的低效δ阿片配体。通过降低δ效率，降低kappa亲和力，并保持高mu效率，将得到具有所需轮廓的orvinols类似物。该方法包括利用一种新的分子建模方法建立三角洲拮抗的药效团模型，以及选择具有合适位置芳香环的靶分子。新模型将通过合成含有满足药效团的芳香族的简单吗啡来测试。从简单吗啡中获得的信息将应用于设计和合成由模型选择的目标5,14桥接吗啡苷基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。本提案的最终目标是开发强效的mu阿片类镇痛药，其耐受性发展缓慢，或根本没有，以减少在临床疼痛的慢性治疗中所见的不良影响。

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.