Design, preparation and biological evaluation of libraries of marocyclic delta opioid receptor agonists for the treatment of pain

这项研究提案的总体目标是提供新型多肽类阿片受体激动剂，用于治疗慢性疼痛。尽管在过去的30年里，已经开发出了许多多肽和非多肽DOPR激动剂，但很少有化合物进入临床试验，最重要的是，目前还没有一种化合物被批准用于临床。这项研究的原创性和新颖性依赖于这样一个事实，即我们将合成新型环脑啡肽类似物的库，这些库最终将提供具有更好的稳定性、更好的传递能力和对DOPR更好的选择性的类药物分子。事实上，我们已经合成了对DOPR具有更好的亲和力的这种大内酰胺类药物，我们的工业合作伙伴Cyclum Pharma将帮助我们准备结构上与我们已经强大的分子相关的环肽的偏向文库。此外，我们对结构-活性和结构-选择性关系的计算分析以及PET成像方法将有助于我们设计文库。

The overall goal of this research proposal is to provide novel peptide-based DOPr (delta opioid receptor) agonists for the treatment of chronic pain. Although numerous peptide and non-peptide DOPr agonists have been developed over the past 30 years, very few compounds have reached clinical trials and, most importantly, nowadays none of them have been approved for clinical use. Originality and novelty of this research proposal relies on the fact that we will synthesize libraries of novel cyclic enkephalin analogs which will ultimately afford drug-like molecules with better stability, enhanced delivery and greater selectivity toward DOPr.As a matter of fact, we already have synthesized such macrolactams with improved affinity for DOPr and our industrial collaborator, Cyclenium Pharma, will help us preparing biased libraries of cyclic peptides structurally related to our already potent molecules. Furthermore, our computational analysis of structure-activity and structure-selectivity relationships and PET imaging approaches will assist us during the design of the libraries.