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

本研究的总体目标是提供新的基于肽的DOPr（δ阿片受体）激动剂用于治疗慢性疼痛。尽管在过去的30年中已经开发了许多肽和非肽DOPr激动剂，但很少有化合物达到临床试验，最重要的是，现在它们中没有一个被批准用于临床使用。这项研究提案的独创性和新奇依赖于这样一个事实，即我们将合成新的环状脑啡肽类似物的文库，这些类似物最终将提供具有更好的稳定性、增强的递送和对DOPr的更大选择性的药物样分子。事实上，我们已经合成了对DOPr具有改善的亲和力的大环内酰胺，我们的工业合作者Cyclenium Pharma，将帮助我们制备结构上与我们已经有效的分子相关的环状肽的偏向文库。此外，我们的结构-活性和结构-选择性关系的计算分析和PET成像方法将有助于我们在图书馆的设计。

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.