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

Sahar S Alghamdi1, Suni M Mustafa1, Bob M Moore Ii1

  • 1Department of Pharmaceutical Sciences, College of Pharmacy, University of Tennessee Health Science Center, Memphis, TN 38163, USA.

Bioorganic & Medicinal Chemistry
|February 7, 2021
PubMed

Insights

Researchers developed novel cannabinoid receptor 2 (CB2) inverse agonists to treat neuroinflammation. Compound 40 effectively shifted microglia from a pro-inflammatory to a pro-wound healing state, advancing therapeutic strategies for neurodegenerative diseases.

Area of Science:

  • Neuroscience
  • Pharmacology
  • Immunology

Background:

  • Microglia drive neuroinflammation in neurodegenerative diseases like Alzheimer's, Parkinson's, and Multiple Sclerosis.
  • Chronic M1 pro-inflammatory microglia up-regulate cannabinoid receptor 2 (CB2) expression.
  • Targeting CB2 offers a therapeutic strategy to modulate microglial phenotype.

Purpose of the Study:

  • To refine the structure-activity relationship of 2,6-dihydroxy-biphenyl-aryl-methanone CB2 inverse agonists.
  • To develop selective CB2 inverse agonists for shifting microglia to an M2 pro-wound healing phenotype.
  • To identify novel compounds for treating neuroinflammatory diseases.

Main Methods:

  • Synthesis of a series of analogs based on the lead compound SMM-189.
  • Measurement of compound affinity, selectivity, potency, and efficacy.
  • Assessment of cAMP production and β-arrestin recruitment.
  • Evaluation of microglial phenotype bias in LPS-stimulated cell lines.

Main Results:

  • Compound 40 showed significantly increased potency and efficacy for cAMP stimulation compared to SMM-189.
  • Compound 40 effectively biased microglia towards an M2 pro-wound healing phenotype.
  • The study advanced the understanding of the structure-activity relationship for the CB2 inverse agonist scaffold.

Conclusions:

  • The 2,6-dihydroxy-biphenyl-aryl-methanone scaffold is a promising basis for developing CB2 inverse agonists.
  • Compound 40 represents a potential therapeutic candidate for neuroinflammatory conditions.
  • Targeting CB2 offers a viable strategy for modulating microglia activation in neurodegenerative diseases.
Keywords:
CB2 receptorCannabinoidsInverse agonistMicrogliaPolarizationcAMPβ-Arrestin

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