Novel, potent THC/anandamide (hybrid) analogs

Bioorg Med Chem. 2007 Dec 15;15(24):7850-64. doi: 10.1016/j.bmc.2007.08.039. Epub 2007 Aug 25.


The structure-activity relationship (SAR) of the end pentyl chain in anandamide (AEA) has been established to be very similar to that of Delta(9)-tetrahydrocannabinol (Delta(9)-THC). In order to broaden our understanding of the structural similarities between AEA and THC, hybrid structures 1-3 were designed. In these hybrids the aromatic ring of THC-DMH was linked to the AEA moiety through an ether linkage with the oxygen of the phenol of THC. Hybrid 1 (O-2220) was found to have very high binding affinity to CB1 receptors (K(i)=8.5 nM), and it is interesting to note that the orientation of the side chain with respect to the oxygen in the phenol is the same as in THCs. To further explore the SAR in this series the terminal carbon of the side chain was modified by adding different substituents. Several such analogs were synthesized and tested for their CB1 and CB2 binding affinities and in vivo activity (tetrad tests). The details of the synthesis and the biological activity of these compounds are described.

MeSH terms

  • Animals
  • Arachidonic Acids / chemistry*
  • Arachidonic Acids / pharmacology
  • Cannabinoid Receptor Agonists*
  • Cell Line
  • Cells, Cultured
  • Dronabinol / analogs & derivatives*
  • Dronabinol / chemistry*
  • Dronabinol / pharmacology
  • Drug Evaluation, Preclinical
  • Endocannabinoids
  • Humans
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Polyunsaturated Alkamides / chemistry*
  • Polyunsaturated Alkamides / pharmacology
  • Structure-Activity Relationship


  • Arachidonic Acids
  • Cannabinoid Receptor Agonists
  • Endocannabinoids
  • Polyunsaturated Alkamides
  • Dronabinol
  • anandamide