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 due to the lack of potent and selective agonists and antagonists of GPR55. Binding assays are not yet available for GPR55 screening and GPR55 signal pathways discrepancies 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 by a label-free cell-impedance based assay using GPR55-HEK293. The real-time impedance responses provide 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 vs classical cannabinoid receptors. Upon antagonist treatment, the chromenopyrazoles 21-24 inhibited lysophosphatidylinositol (LPI) effect. One of these GPR55 antagonists (21) is fully selective vs classic cannabinoid receptors. Compared to LPI, predicted physicochemical parameters of the new compounds suggest a clear pharmacokinetic improvement.