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Paula Morales, Pilar Goya, Nadine Jagerovic
Figure 4. Structure and affinity of the three more potent and selective CB1R ligands of the first chromenopyrazole series
(18).
In a further approach to evaluate the therapeutic
potential of the peripheral CB1R agonist 8a, this
chromenopyrazole was tested in a rat model of orofacial
pain. Interestingly, compound 8a showed a remarkable
antinociceptive response probably mediated by peripheral
mechanisms.
To sum up, in this study, the chromenopyrazole
scaffold was reported for the first time opening new
avenues in the cannabinoid chemistry scenario. Among
this first series of chromenopyrazoles, non-psychoactive
and selective CB1R agonists with peripheral
antinociceptive properties were identified (18).
3. TOWARDS CB2R SELECTIVITY: APPLICATION
IN NEURODEGENERATIVE DISEASES
A second approach to pursue the separation of the
therapeutic effects of cannabinoids from their psychotropic
effects is the search of CB2R selective ligands. Although
CB1R is the main receptor of the CNS, the presence of
CB2R in microglia and neuronal cells as well as its role in
the immune system (20–22), suggest the possibility to use
CB2R agonists to treat certain neurological conditions
without psychotropic unwanted effects (23,24). The role of
the CB2R in the CNS is closely related to neuronal
damage, particularly inflammatory. Therefore, as
suggested by numerous studies, CB2R represents a
promising target for alleviating the neuronal deterioration
and neuroinflammation triggered by neurodegenerative
diseases (5,23).
In an attempt to target the CB2R, different structural
modifications on the chromenopyrazole scaffold were
accomplished while retaining the 1,1-dimethylheptyl
aliphatic chain that provided better results in the previous observed for the chromenopyrazoles.
study. In this case, the conversion of the phenolic
hydroxyl, a pharmacophoric moiety of classical
168 @Real Academia Nacional de Farmacia. Spain
cannabinoids, to different alkoxy groups was explored.
Moreover, different pyrazole substituents as well as
bioisosteric replacement of the pyrazole by an isoxazole
were also intended for further fine-tuning of CBRs affinity
and selectivity (25).
The synthesis of these chromenopyrazoles has been
reported to be achieved by alkylation of the phenolic
oxygen of the chromenopyrazoles described in the
previous section with the corresponding alkyl halides. The
bioisosteric replacement by an isoxazole moiety, was
obtained upon condensation of the ß-ketoaldehyde (4) with
hydroxylamine hydrochloride (25).
Figure 5 provides an overview of the affinity trends
that can be featured from the radioligand binding assays of
these chromenopyrazoles at the cannabinoid receptors
CB1R and CB2R (25). As detailed in the previous section,
chromenopyrazoles bearing a free phenolic hydroxyl group
display CB1R affinity and selectivity. Phenolic alkylation
of these compounds causes a drastic loss of CB1R affinity,
whereas high CB2R selectivity was achieved with
alkoxychromenopyrazoles derivatives. These results
suggest that the phenolic hydroxyl may play a crucial role
in CBR selectivity.
Another relevant conclusion extracted from reported
structure-activity relationship (SAR) is that the nature of
the pyrazole substituent influences the affinity for the
cannabinoid receptors. In general, alkyl groups showed
better affinity for CB2R compared to aryl substituents.
Bioisosteric replacement of the pyrazole by an isoxazole
results in cannabinoid ligands with affinity in the
nanomolar range. Upon phenolic alkylation,
chromenoisoxazoles follow the same affinity pattern