2. Academic Validation
  3. Novel Tetraolefinic Chain Phenyl Substituted Endocannabinoid Probes

Novel Tetraolefinic Chain Phenyl Substituted Endocannabinoid Probes

  • J Med Chem. 2025 Jul 10;68(13):13376-13392. doi: 10.1021/acs.jmedchem.5c00047.
Markos-Orestis Georgiadis 1,  Lipin Ji 1,  Fei Tong 1,  Vuong Q Dang 2,  Luana Assis Ferreira 3,  Alexandra Faragher 2,  Ngan Tran 1,  Anastasiia V Sadybekov 4,  Suthakar Ganapathy 1,  Nikolai Zvonok 1,  Vsevolod Katritch 4,  Andrea G Hohmann 3 5 6,  Laura M Bohn 2,  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 Department of Molecular Medicine, The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology, Jupiter, Florida 33458, United States.
  • 3 Psychological and Brain Sciences, Indiana University, Bloomington, Indianna, 47405, 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, Indianna, 47405, United States.
  • 6 Gill Institute of Neuroscience, Indiana University, Bloomington, Indianna, 47405, United States.
  • 7 Center for Drug Discovery and Department of Chemistry and Chemical Biology, Northeastern University, Boston, Massachusetts 02115, United States.
PMID: 40569175 DOI: 10.1021/acs.jmedchem.5c00047
Abstract

We report the development of novel endocannabinoid analogs carrying phenyl rings in judiciously chosen positions within the tetraolefinic chain pharmacophore of the endogenous N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG). Key successful analogs were found to exhibit remarkably high binding affinity and potency for cannabinoid receptors. Importantly, among the reported SAR studies of endocannabinoids, as well as mono- and poly unsaturated fatty acid derivatives, the current work is the first to show that the nonconjugated Z double bonds of a polyunsaturated fatty acid signaling molecule can be replaced by phenyl rings, the most common framework in marketed drugs. Our SAR results are supported by docking studies of the key analogs on the crystal structures of CB1 and CB2 receptors. When tested in vivo, our key analog AM11638 behaves as a more potent and longer lasting analgesic than the endogenous anandamide. Stereoselective procedures for the demanding syntheses of the new analogs are described.

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