Page 60 - 84_02
P. 60
The chromenopyrazole scaffold in the modulation of the endocannabinoid system: a broad therapeutic prospect
energy values. Photophysical properties of the modulators from different origins have been reported in
chromenopyrazole conjugate 14 showed stronger the literature. A structural update of these GPR55 ligands
absorption intensity for both Soret (420 nm) and Q-bands have been recently described in a review (107). GPR55
than the free TPP (500-700 nm). These data are suitable ligands include endogenous molecules such as 2-
for a photosensitizer considering that an ideal arachidonoyl-L-a-lysophosphatidylinositol (2-AGPI), N-
photosensitizer should have high absorption with arachidonyl glycine (NAGly) (109), and anandamide
wavelengths between 600 and 800 nm, no shorter than 600 (AEA). The regulation of GPR55 activity by a range of
nm for tissue penetration and no longer than 800 nm to phytocannabinoids and synthetic derivatives has been
provide enough energy to excite oxygen to its singlet state. described but in some cases it is still controversial (107).
In what refers to the cannabinoid properties of this For instance, ?9-THC was found to be effective activating
porphyrin/chromenopyrazole conjugate, it has been GPR55 in [35S]GTP?S binding, RhoA assays and
described to bind weakly but selectively to CB2R. intracellular calcium mobilization in transiently transfected
hGPR55-HEK293 cells, whereas it was unable to stimulate
In summary, a porphyrin-chromenopyrazole conjugate ERK1/2 phosphorylation nor ß-arrestin recruitment.
has been designed and synthesized even though the Cannabidiol, reported as GPR55 antagonist in [35S]GTP?S
syntheses of porphyrin derivatives are known to be binding and Rho activation assays, resulted to be inactive
tedious. The reported photophysical and pharmacological in Ca2+ mobilization and ß-arrestin recruitment
properties are suitable for a potential activity as antitumor experiments.
agent.
Among the large number of synthetic cannabinoids
5. CHROMENOPYRAZOLES AS GPR55 reported so far, some of them showed to have relevant
MODULATORS activity at GPR55. Curiously, despite their structural
diversity, in each family it has been possible to find
The orphan G protein-coupled receptor GPR55 (105) GPR55 modulators (107). The CB1R/CB2 R agonist CP-
has been proposed as one of the missing cannabinoid 55,940, a cyclohexylphenoxy derivative, displayed GPR55
receptor types even though it shares low identity with agonism in [35S]GTP?S evaluation and GPR55 antagonist
CB1R and CB2R (106). GPR55 has been related to the in ß-arrestin, ERK phosphorylation and calcium
endocannabinoid system since CB1R and CB2R ligands mobilization assays. Several diarylpyrazoles such as the
from diverse origins, endogenous, natural, and synthetic, CB1R antagonist rimonabant, or aminoalkylindoles
can modulate this receptor. Over these last years, its exemplified by WIN55,212-2 interact with GPR55.
complex cellular signaling pathways and biological Coumarin and magnolol cannabinoids have also been
functions have been the focus of numerous studies (107) proposed as GPR55 scaffold.
that identified GPR55 as a promising target for the
treatment of various pathologies such as inflammation, Few non-CB1R/CB2R-related GPR55 ligands have
neuropathic pain, bone physiology, diabetes and cancer. been reported so far (107). High throughput screening of a
However, GPR55 validation as a therapeutic target is far library of compounds from the Sandford-Burnham
from being confirmed due to the complexity of GPR55 screening center of the Molecular Libraries Probe
downstream signaling and the lack of potent and selective Production Centers Network (MLPCN) allowed the
GPR55 agonists and antagonists. Effectively, GPR55 identification of different GPR55 scaffolds (110)
couples to different G-proteins, Ga13, Gaq/11, Gaq /Ga12 or exemplified by triazoloquinoline CID1172084,
Ga12/13 depending on the cell type and GPR55 modulator. thienopyrimidine CID1434953, and pyrrolopyrazolone
For instance, stimulation of the Gaq subunit involves the CID16020046 (figure 12). Data resulting from this
phospholipase C with intracellular calcium release with screening realized with ß-arrestin assays in U2OS cells
possible activation of the MAPK/ERK signaling, whereas permanently expressing HA-GPR55E and ßarr2-GFP,
the Ga12/13 subunit preferably influences the RhoA/ROCK were confirmed by other biochemical tests from
signaling pathway. independent studies.
L-a-lysophosphatidylinositol (LPI) has been suggested
to be a GPR55 endogenous ligand (108). GPR55
@Real Academia Nacional de Farmacia. Spain 175
