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The chromenopyrazole scaffold in the modulation of the endocannabinoid system: a broad therapeutic prospect
mediated GPR55 stimulation was also assessed and epilepsy, anxiety disorders, and schizophrenia is
reported. Upon antagonist treatment, three of the highlighted by numerous preclinical studies (115). Clinical
chromenopyrazoles of series II inhibited LPI effect (1 trials are already on going for treatment-resistant seizure
µM), being one of them fully selective versus CB1R and disorders such as Lennox-Gastaut and Dravet syndromes
CB2R. These studies allowed a tuning of compound and for the treatment of inflammatory bowel diseases
properties that was achieved by small modifications of the among others (116).
substitution pattern.
Despite the therapeutic interest of CBD, only few CBD
Additional xCELLigence experiments performed in derivatives have been reported (117). The structural
HEK293 cells with active chromenopyrazoles from both modifications of CBD have been realized on the pentyl
series allowed to confirm that the cellular responses chain introducing heteroatoms or modifying the length of
observed in hGPR55-HEK293 cells were mediated the alkyl chain, on the substituents of the cyclohexene, and
through GPR55. on the cyclohexene itself using bioisosterism with
cyclopentane or cyclohexane for instance. Replacement of
Administration, distribution, and metabolism (ADME) the cyclohexene by a nitrogenated-heterocycle has been
properties of the active chromenopyrazoles were predicted reported in 1983 with the synthesis of 5-pentyl-2-
in silico using a set of 34 physicochemical descriptors (pyrrolidin-2-yl)benzene-1,3-diol (118), and more recently
computed by QikProp. According to this first approach, with the preparation of 5-alkyl-2-(1H-pyrazol-5-
the predicted parameters suggest pharmacokinetic yl)benzene-1,3-diols which are related to the
improvements compared to LPI that is very insoluble in chromenopyrazole scaffold (figure 14) (117).
water, air and light sensitive.
In summary, among the new proposed GPR55
scaffolds, chromenopyrazole was proposed to constitute a
versatile scaffold for obtaining potent GPR55 modulators.
Moreover, evaluation of these chromanopyrazoles at
GPR55 was described in a cell-impedance-based assay
integrating complex signaling pathways involved in
GPR55 activation.
6. NOVEL CANNABIDIOL DERIVATIVES Figure 14. CBD derivatives based on chromenopyrazole
scaffold.
Cannabidiol (CBD) (113) and ?9-THC are the two
major phytocannabinoids isolated from Cannabis Sativa. Two synthetic route have been reported for the
CBD and ?9-THC are biosynthesized through the same synthesis of these 5-alkyl-2-(1H-pyrazol-5-yl)benzene-1,3-
metabolic pathway from cannabigerolic acid at the diols illustrated in scheme 2. A Friedel-Crafts acylation of
exception of the last step catalyzed by different enzymes, the appropriate 3,5-dimethoxyresorcinol followed by a–
CBDA and THCA synthase respectively. Whereas there is formylation and reaction with hydrazine constitutes the
a clear structural relationship between both structures, their first synthetic route (scheme 2: Route A). In the second
pharmacology differs considerably. For instance, CBD synthetic route, 5-dimethylheptyl-2-(1H-pyrazol-5-
does not induce the psychotropic effects associated to ?9- yl)benzene-1,3-diol 20 is prepared by reacting hydrazine
THC. Moreover, the complex pharmacology of CBD has with a chromone previously synthesized from the
not been fully elucidated yet. CBD shows only low affinity resorcinol olivetol by a succession of acylation and
for the cannabinoid receptors CB1R and CB2R, but it hydrolysis to 5-pentyl-2-(1H-pyrazol-5-yl)benzene-1,3-
modulates indirectly the endocannabinoid system through diol 23 (scheme 2: Route B). These two synthetic
fatty acid-binding proteins (FABPs), transient receptor approaches led to new CBD derivatives which
potential vanilloid type 1 (TRPV1), 5-hydroxytryptamine pharmacological evaluation has not been reported so far.
subtype 1A receptor (5-HT1A), peroxisome proliferator-
activated receptor ? (PPAR-?), and the A1A adenosine
receptor (114).
The therapeutic potential of CBD for
neurodegenerative diseases, inflammation-related diseases,
@Real Academia Nacional de Farmacia. Spain 177
