Cannabinol derivatives: Binding to cannabinoid receptors and inhibition of adenylylcyclase

Several derivatives of cannabinol and the 1,1-dimethylheptyl homolog (DMH) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB₁ and CB₂), as well as for activation of CB₁- and CB₂-mediated inhibition of adenylylcyclase. The DMH derivatives were much more potent than the pentyl (i.e., cannabinol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potently to both CB₁ and CB₂ (K(i) values of 38.0 ± 7.2 and 26.6 ± 5.5 nM, respectively) and to inhibit CB₁-mediated adenylylcyclase with an EC₅₀ of 58.1 ± 6.2 nM but to cause only 20% inhibition of CB₂-mediated adenylylcyclase at 10 μM. It behaves as a specific, though not potent, CB₂ antagonist. 11- Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB₁ and CB₂ (K(i) values of 100 ± 50 and 200 ± 40 pM; EC₅₀ of adenylylcyclase inhibition 56.2 ± 4.2 and 207.5 ± 27.8 pM, respectively).