CANNABINOL DERIVATIVES - BINDING TO CANNABINOID RECEPTORS AND INHIBITION OF ADENYLYLCYCLASE

Several derivatives of cannabinol anti the 1,1-dimethylheptyl homolog (DMM) of cannabinol were prepared and assayed for binding to the brain and the peripheral cannabinoid receptors (CB1 and CB2), as well as fo r activation of CB1- and CB2-mediated inhibition of adenylylcyclase. T he DMH derivatives were much more potent than the pentyl (i.e., cannab inol) derivatives. 11-Hydroxycannabinol (4a) was found to bind potentl y 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 EC5 0 of 58.1 +/- 6.2 nM but to cause only 20% inhibition of CB2-mediated adenylylcyclase at 10 mu M. It behaves as a specific, though not poten t, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agon ist 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).