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Paula Morales, Pilar Goya, Nadine Jagerovic
Figure 1. Structure of selected cannabinoid ligands: phytocannabinoids (?9-THC, CBN, and CBD); endocannabinoids
(AEA and 2-AG); synthetic derivatives (CP55,940, WIN55,212-2 and SR141716A).
The chromenopyrazole appears in the field of
cannabinoid analogues in 1985, before the discovery of the
cannabinoid receptors (17). The authors described them as
heterocyclic-fused benzopyrans, reported their synthesis,
and concluded that these compounds had no interesting
levels of activity in the CNS. In 2012, the
chromenopyrazole scaffold was re-explored as a
cannabinoid chemotype taking advantage of the progress
realized in the understanding of the ECS (figure 2). This
tricyclic structure was designed in analogy to the classical
cannabinoid cannabinol (CBN), bearing a benzopyran
moiety but exploring for the first time the contribution of a PAIN
pyrazole ring in place of the CBN´s phenyl group.
Figure 2. General structural features of the
chromenopyrazole scaffold.
Since then, different strategies to target the ECS under
diverse pathological conditions have driven the exploration
166 @Real Academia Nacional de Farmacia. Spain
of structural modifications of this tricyclic core. Structure-
activity relationships as well as the rational understanding
of ligand-receptor interactions helped fine-tuning the
potential of the chromenopyrazole scaffold targeting
diverse pathological conditions. This work, critically
reviews the findings obtained so far offering future
perspectives for the use of this versatile scaffold to
continue unraveling the complex pharmacology of the
ECS.
2. CB1R SELECTIVE LIGANDS: APPLICATION IN
As previously mentioned, the psychotropic side-effects
of cannabinoid receptor agonists have limited their
exploitation as medications. These unwanted properties are
mediated by the CB1Rs located in the CNS, therefore, a
strategy to selectively target CB1Rs located outside the
brain is the development of peripherally restricted ligands.
In an effort to identify novel cannabinoids, the
chromenopyrazole scaffold was discovered by introducing
a pyrazole ring to the benzopyran core of classical
phytocannabinoids (18). The synthesis of these reported
molecules is summarized in scheme 1.