Journal
BIOORGANIC & MEDICINAL CHEMISTRY
Volume 33, Issue -, Pages -Publisher
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2021.116035
Keywords
Cannabinoids; Inverse agonist; CB2 receptor; cAMP; beta-Arrestin; Microglia; Polarization
Funding
- Plough Center for Sterile Drug Delivery Systems, University of Tennessee Health Science Center
- King Saud Bin Abdul Aziz University for Health Sciences (KSAU-HS) Riyadh, Saudi Arabia
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Research focuses on CB2 as a therapeutic target for neuroinflammatory diseases, aiming to shift microglia bias to a pro-wound healing phenotype. Compound 40 demonstrates increased potency and efficacy for cAMP stimulation compared to SMM189, effectively biasing microglia towards a pro-wound healing phenotype.
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 beta-arrestin recruitment. In this series compound 40 demonstrated a significant increase in potency and efficacy for cAMP stimulation compared to SMM189. 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.
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