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antinociceptive properties (18). Structural modifications
of the chromenopyrazole core allowed fine-tuning of
cannabinoid receptor affinity and activity. Structural
features required for CB1R/CB2R affinity and selectivity
were determined using molecular modeling. These
studies led to the identification of a potent and selective allowing the discovery of novel chromenopyrazole
CB2R agonist with confirmed neuroprotective properties
in murine models of neurodegenerative disorders (25,26).
Further exploration of this scaffold allowed the
design of multifunctional chromenopyrazoles. This
strategy involved targeting different anticancer modes of
action in a single molecule. The antitumor properties of
cannabinoids and the redox properties characterizing
quinones were fused in chromenopyrazolediones (figura
15). The antiproliferative activity of these new
compounds was successfully explored in vitro and in vivo
in breast and prostate cancer models (63,64).
Figure 15. Summary of the chromenopyrazole derivatives reported so far and their pharmacological profile.
New chromenopyrazoles could be synthesized and
screened against other relevant biological targets of the
endocannabinoid system or related targets. Apart from the
potential of chromenopyrazoles as therapeutic agents, they
also should be considered tools to validate new biological
targets.
@Real Academia Nacional de Farmacia. Spain
The chromenopyrazole scaffold was also exploited
for the modulation of the putative cannabinoid receptor
GPR55. Two series of compounds have been reported
(112). Their ability to activate GPR55 was measured
through an innovative label-free cell impedance assay
GPR55 partial agonists and antagonists.
The last approach pursued in the exploration of this
scaffold is the development of CBD-related
chromenopyrazoles (117). Even though their therapeutic
potential has not been reported yet, the nature of its
resorcinol core may provide interesting antioxidant
properties. Possible activity at cannabinoid related targets
such as GPR3, GPR6, GPR12, GPR55 or GPR18 should
be considered when evaluating this compound since CBD
modulates all of them with moderate potencies (124–
127).
Activation of the CB1R and CB2R has been shown to
induce different cellular signaling cascades through
coupling to different effector proteins: G-protein (Gai/o)
and ß-arrestins (1/2) (128–130). The search for a ligand
that can induce specific receptor activation profiles
resulting in specific subsets of signaling pathways (biased
179