Cannabidiolic Acid as a Selective Cyclooxygenase-2 Inhibitor

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

ABSTRACT:
In the present study it was revealed that cannabidiolic acid (CBDA) selectively
inhibited cyclooxygenase-2 (COX-2) activity with an IC50 value (50% inhibition
concentration) around 2 µM, having 9-fold higher selectivity than COX-1
inhibition. In contrast, ∆9
-tetrahydrocannabinolic acid (∆9
-THCA) was a much less
potent inhibitor of COX-2 (IC50 > 100 µM). Nonsteroidal anti-inflammatory drugs
containing 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 assumed that the whole structure of CBDA is
important for COX-2 selective inhibition, since
DMD #20909
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Introduction
Cannabis is one of the oldest known medicinal plants and produces
pharmacologically important substances. Among them, most important are the
cannabinoids that are unique components in the cannabis plant.
∆9
-Tetrahydrocannabinol (∆9
-THC) and cannabidiol (CBD) are known to be major
cannabinoids in the plant. ∆9
-THC is known to have pharmacological effects such
as psychoactivity and hallucination (Dewey, 1986; Howlett et al., 2002)
Cannabinoids (i.e., ∆9
-THC and CBD) are also being used as a rheumatoid
arthritis agent in clinical settings (Klein and Newton, 2007) because of their
anti-inflammatory effects (Formukong et al., 1998). In fresh plant materials, most
of ∆9
-THC and CBD exist as their respective acid forms,
∆9
-tetrahydrocannabinolic acid (∆9
-THCA) and cannabidiolic acid (CBDA)
(Yamauchi et al., 1967; Turner et al., 1980; Taura et al., 2007). The specific use of
acidic cannabinoids including ∆9
-THCA and CBDA, as the active pharmaceutical
ingredients, is not disclosed to date since these acid forms of cannabinoids are
recognized as pharmacologically inactive forms (Yamauchi et al., 1967; Razdan,
1986; Burstein, 1999). By focusing on the structures between ∆9
-THCA and
CBDA, it was revealed that both acidic cannabinoids have a salicylic acid moiety
in their structures (Fig. 1). Salicylic acid is known to be an inhibitor of
cyclooxygenases

Source dmd.aspetjournals.org/content/dmd/early/2008/06/12/dmd.108.020909.full.pdf

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