Identification of Novel GPR55 Modulators Using Cell-Impedance-Based Label-Free Technology

The orphan G protein-coupled receptor
GPR55 has been proposed as
a novel receptor of the endocannabinoid system. However, the validity
of this categorization is still under debate mainly because of the
lack of potent and selective agonists and antagonists of GPR55. Binding
assays are not yet available for GPR55 screening, and discrepancies
in GPR55 mediated signaling pathways have been reported. In this context,
we have designed and synthesized novel GPR55 ligands based on a chromenopyrazole
scaffold. Appraisal of GPR55 activity was accomplished using a label-free
cell-impedance-based assay in hGPR55-HEK293 cells. The real-time impedance
responses provided an integrative assessment of the cellular consequence
to GPR55 stimulation taking into account the different possible signaling
pathways. Potent GPR55 partial agonists (14b, 18b, 19b, 20b, and 21–24) have been identified; one of them (14b) being
selective versus classical cannabinoid receptors. Upon antagonist
treatment, chromenopyrazoles 21–24 inhibited lysophosphatidylinositol (LPI) effect. One of these GPR55
antagonists (21) is fully selective versus classic cannabinoid
receptors. Compared to LPI, the predicted physicochemical parameters
of the new compounds suggest a clear pharmacokinetic improvement.