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 (Ki 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 microM. It behaves as a specific, though not potent, CB2 antagonist. 11-Hydroxycannabinol-DMH (4b) is a very potent agonist for both CB1 and CB2 (Ki values of 100 +/- 50 and 200 +/- 40 pM; EC50 of adenylylcyclase inhibition 56.2 +/- 4.2 and 207.5 +/- 27.8 pM, respectively).
Rhee
M H
MH
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel.
Vogel
Z
Z
Barg
J
J
Bayewitch
M
M
Levy
R
R
Hanus
L
L
Breuer
A
A
Mechoulam
R
R
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001921:Brain / Q000378:metabolism; D016466:CHO Cells; D019556:COS Cells; D002186:Cannabinoids / Q000737:chemistry / Q000378:metabolism; D002187:Cannabinol / Q000031:analogs & derivatives* / Q000378:metabolism; D002375:Catalepsy / Q000139:chemically induced; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D051379:Mice; D008956:Models, Chemical; D051381:Rats; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D014162:Transfection
D000067956:Adenylyl Cyclase Inhibitors; D002186:Cannabinoids; C469526:Cnr2 protein, rat; D004791:Enzyme Inhibitors; D043885:Receptor, Cannabinoid, CB2; D043882:Receptors, Cannabinoid; D011955:Receptors, Drug; C078815:HU 243; D002187:Cannabinol