2. Academic Validation
  3. Exceptionally Potent Chiral Anandamide Analogs

Exceptionally Potent Chiral Anandamide Analogs

  • J Med Chem. 2025 Sep 15. doi: 10.1021/acs.jmedchem.5c02030.
Markos-Orestis Georgiadis 1,  Elena Ferreras 1,  Lipin Ji 1,  Luana Assis Ferreira 2,  John Hainline 2,  Fei Tong 1,  Vuong Q Dang 3,  Alexandra Faragher 3,  Anastasiia V Sadybekov 4,  Laura M Bohn 3,  Vsevolod Katritch 4,  Andrea G Hohmann 2 5 6,  Alexandros Makriyannis 1 7,  Spyros P Nikas 1
Affiliations

Affiliations

  • 1 Center for Drug Discovery and Department of Pharmaceutical Sciences, Northeastern University, Boston, Massachusetts 02115, United States.
  • 2 Psychological and Brain Sciences, Indiana University, Bloomington, Indiana 47405, United States.
  • 3 Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida 33458, United States.
  • 4 Department of Quantitative and Computational Biology, and Department of Chemistry, Bridge Institute, Center for New Technologies in Drug Discovery and Development, University of Southern California, Los Angeles, California 90089, United States.
  • 5 Program in Neuroscience, Indiana University, Bloomington, Indiana 47405, United States.
  • 6 Gill Institute of Neuroscience, Indiana University, Bloomington, Indiana 47405, United States.
  • 7 Center for Drug Discovery and Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
PMID: 40954107 DOI: 10.1021/acs.jmedchem.5c02030
Abstract

We recently reported an innovative design approach that allowed us to obtain potent endocannabinoids with enhanced metabolic stability. Our design is characterized by the incorporation of chiral centers within the endocannabinoid prototypes N-arachidonoylethanolamide and 2-arachidonoylglycerol. Work on N-arachidonoylethanolamide led to the identification of the first-generation lead analog (R)-N-(1-Methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AMG315). Here, we synthesized a series of tail-modified AMG315 analogs to further optimize this novel chemotype for Cannabinoid Receptor binding affinity and potency. Our advanced molecule, namely, 20,20,20-trifluoro-(R)-N-(1-methyl-2-hydroxyethyl)-13-(S)-methyl-arachidonamide (AM12814, 12), is the first endocannabinoid analogue exhibiting unprecedented affinity for both the CB1 and CB2 receptors. In further in vitro functional characterization, 12 behaves as a potent, partial CB1 and CB2 Agonist. Our SAR results are supported by docking studies of 12 on the crystal structures of cannabinoid receptors, while when tested in vivo, 12 behaves as a very potent and efficacious CB1 Agonist. This analogue will serve as a unique endocannabinoid probe.

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