Microglia are the principle cell type driving sustained neuroinflammation in neurodegenerative diseases such as Alzheimer’s, Parkinson’s, and Multiple Sclerosis. Interestingly, microglia locked into a chronic M1 pro-inflammatory phenotype significantly up-regulate the cannabinoid receptor 2 (CB2) expression. Our approach to exploiting CB2 as a therapeutic target in neuroinflammatory diseases focuses on the development of selective CB2 inverse agonists to shift microglia bias to a M2 pro-wound healing phenotype. Herein we report work designed to refine the structure activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone CB2 inverse agonist scaffold. A series of analogs of our lead compound SMM-189 were synthesized and measured for affinity/selectivity, potency, and efficacy in regulating cAMP production and β-arrestin recruitment. In this series compound 40 demonstrated a significant increase in potency and efficacy for cAMP stimulation compared to SMM-189. Akin to our lead SMM-189, this compound was highly efficacious in biasing microglia to an M2 pro-wound healing phenotype in LPS stimulated cell lines. These results advance our understanding of the structure-activity relationship of the 2,6-dihydroxy-biphenyl-aryl-methanone scaffold and provide further support for regulating microglia activation using CB2 inverse agonists.

小胶质细胞是导致神经退行性疾病（如阿尔茨海默病、帕金森病和多发性硬化症）持续神经炎症的主要细胞类型。有趣的是，小胶质细胞锁定为慢性 M1 促炎表型，显着上调大麻素受体 2 (CB2) 的表达。我们利用 CB2 作为神经炎症疾病治疗靶点的方法侧重于开发选择性 CB2 反向激动剂，以将小胶质细胞偏向性转变为 M2 促进伤口愈合表型。在此，我们报告了旨在改进 2,6-二羟基-联苯-芳基-甲酮 CB2 反向激动剂支架的结构活性关系的工作。合成了我们先导化合物 SMM-189 的一系列类似物，并测量了其在调节 cAMP 产生和 β-抑制蛋白募集方面的亲和力/选择性、效力和功效。40证明与 SMM-189 相比，cAMP 刺激的效力和功效显着增加。类似于我们的先导 SMM-189，该化合物在使 LPS 刺激的细胞系中的小胶质细胞偏向 M2 促进伤口愈合表型方面非常有效。这些结果促进了我们对 2,6-二羟基-联苯-芳基-甲酮支架的构效关系的理解，并为使用 CB2 反向激动剂调节小胶质细胞活化提供了进一步的支持。