Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitory Component in Cannabis

ABSTRACT:

In the present study it was revealed that cannabidiolic acid (CBDA) selectively inhibited cyclooxygenase (COX)-2 activity with an IC50 value (50% inhibition concentration) around 2 M, having 9-fold higher selectivity than COX-1 inhibition. In contrast, 9-tetrahydro- cannabinolic acid ( 9-THCA) was a much less potent inhibitor of COX-2 (IC50 > 100 M). Nonsteroidal anti-inflammatory drugs con- taining a carboxyl group in their chemical structures such as salicylic acid are known to inhibit nonselectively both COX-1 and COX-2. CBDA and 9-THCA have a salicylic acid moiety in their structures. Thus, the structural requirements for the CBDA- mediated COX-2 inhibition were next studied. There is a structural difference between CBDA and 9-THCA; phenolic hydroxyl groups of CBDA are freed from the ring formation with the terpene moiety, although 9-THCA has dibenzopyran ring structure. It was as- sumed that the whole structure of CBDA is important for COX-2 selective inhibition because -resorcylic acid itself did not inhibit COX-2 activity. Methylation of the carboxylic acid moiety of CBDA led to disappearance of COX-2 selectivity. Thus, it was suggested that the carboxylic acid moiety in CBDA is a key determinant for the inhibition. Furthermore, the crude extract of cannabis contain- ing mainly CBDA was shown to have a selective inhibitory effect on COX-2. Taken together, these lines of evidence in this study sug- gest that naturally occurring CBDA in cannabis is a selective inhibitor for COX-2.