Synthesis and biological evaluation of a ring analogs of the selective CB2 inverse agonist SMM-189

Abstract

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.

Keywords: CB2 receptor; Cannabinoids; Inverse agonist; Microglia; Polarization; cAMP; β-Arrestin.