Synthesis, Biological Evaluation, and Molecular Modeling Studies of 3,4-Diarylpyrazoline Series of Compounds as Potent, Nonbrain Penetrant Antagonists of Cannabinoid-1 (CB1R) Receptor with Reduced Lipophilicity

J Med Chem. 2022 Feb 10;65(3):2374-2387. doi: 10.1021/acs.jmedchem.1c01836. Epub 2022 Jan 27.


In the present report, we describe the synthesis and structure-activity relationships of novel "four-arm" dihydropyrazoline compounds designed as peripherally restricted antagonists of cannabinoid-1 receptor (CB1R). A series of racemic 3,4-diarylpyrazolines were synthesized and evaluated initially in CB1 receptor binding assays. The novel compounds, designed to limit brain penetrance and decreased lipophilicity, showed high affinity for CB1R and potent in vitro CB1R antagonist activities. Promising compounds with potent CB1R activity were evaluated in tissue distribution studies. Compounds 6a, 6f, and 7c showed limited brain penetrance attesting to its peripheral restriction. The 4S-enantiomer of these compounds further showed a stereoselective affinity for the CB1 receptor and behaved as inverse agonists. In vivo studies on food intake and body weight reduction in diet-induced obese (DIO) mice showed that these compounds could serve as potential leads for the development of selective CB1R antagonists with improved potency and peripheral restriction.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Anti-Obesity Agents / chemical synthesis
  • Anti-Obesity Agents / metabolism
  • Anti-Obesity Agents / therapeutic use*
  • Body Weight / drug effects
  • Brain / metabolism
  • Cannabinoid Receptor Antagonists / chemical synthesis
  • Cannabinoid Receptor Antagonists / metabolism
  • Cannabinoid Receptor Antagonists / therapeutic use*
  • Diet, High-Fat
  • Drug Inverse Agonism
  • Hydrophobic and Hydrophilic Interactions
  • Male
  • Mice, Inbred C57BL
  • Molecular Structure
  • Obesity / drug therapy*
  • Pyrazoles / chemical synthesis
  • Pyrazoles / metabolism
  • Pyrazoles / therapeutic use*
  • Receptor, Cannabinoid, CB1 / metabolism*
  • Stereoisomerism
  • Structure-Activity Relationship


  • Anti-Obesity Agents
  • Cannabinoid Receptor Antagonists
  • Pyrazoles
  • Receptor, Cannabinoid, CB1