Pharmacological characterization of the GPR17 receptor dual profile

The GPR17 receptor is a G protein-coupled receptor (GPCR) that seems to respond to two unrelated families of endogenous ligands: nucleotide sugars (UDP, UDP-galactose, and UDP-glucose) and cysteinyl leukotrienes (LTD4, LTC4, and LTE4), with significant affinity at micromolar and nanomolar concentrations, respectively [1]. In fact, it interacts with LTD4 (EC50 3.15 nM) and UDP (EC50 1,779 nM), a cysteinyl-leukotriene and a purinergic receptor agonist, respectively. GPR17 activation leads to both adenylyl cyclase inhibition and intracellular calcium decrease. This receptor, which is highly expressed in organs typically undergoing ischemic damage, plays a key role in the progression of brain injury and cell damage repair. GPR17 has been proposed as a potential pharmacological target for the treatment of multiple sclerosis and traumatic brain injury in humans. In order to pharmacologically characterize the dual profile of GPR17, a new compound designed and synthesized to be able to interact with both the binding sites present in the receptor was tested in comparison with known nucleotides and cysteinyl-leukotriene agonists and antagonists. The experiments were performed using the GloSensor™ cAMP assay that allows to monitor GPCR activity through change in the intracellular cAMP concentration (Figure 1).