G-protein-dependent activation of phospholipase C by adenosine A3 receptors in rat brain

Role of adenosine A3 receptors on CA1 hippocampal neurotransmission during oxygen–glucose deprivation episodes of different duration

“…The activation of phospholipase C by adenosine A 3 receptors has been reported in striatal and hippocampal slices [46]. Rat cortical neurons exposed to hypoxia in vitro show an increase in activation of protein kinase C (PKC) after selective A 3 receptor stimulation [47].…”

The Identification of the 2-Phenylphthalazin-1(2H)-one Scaffold as a New Decorable Core Skeleton for the Design of Potent and Selective Human A3 Adenosine Receptor Antagonists

“…Examining the binding results reported in Table 1, it appears that we have identified some new potent and selective adenosine hA 3 receptor antagonists belonging to the 2-phenylphtalazin-1(2H)-one series. In particular, it has to be noted that compounds 12-14, 18, and 19 bearing a methoxyphenyl-or a benzyl-substituted ureido moiety at position 4 are those endowed with high affinity and also selectivity toward the hA 3 receptor, as they are on the whole unable to bind at all the others ARs.…”

“…As reported in the Experimental Section, among the four different types of programs used to calibrate our docking protocol, the Gold program was finally chosen since it showed the best performance with regards to the calculated root-mean-square deviation (rmsd) values relative to the crystallographic pose of ZM241385. 29 Consequently, on the basis of the selected docking protocol, we performed docking simulations to identify the hypothetical binding modes of the newly synthesized 2-phenylphthalazin-1(2H)-one derivatives and of two previously reported TQX and QZ derivatives, inside the hA 3 …”

“…The classical transduction intracellular pathways associated with AR stimulation are inhibition, via G i/o protein (A 1 and A 3 subtypes), or activation, via G s protein (A 2A and A 2B receptors), of adenylate cyclase (AC). 1 More recently, other second messenger systems, such as phospholipase C 3 or potassium 4 and calcium channels, 4,5 have been described as relevant for AR signaling.…”

“…Interest for this new series was driven by the structural similarity between the PHTZ skeleton and both the 2-aryl-1,2,4-triazolo [4,3-a]quinoxalin-1-one (TQX) and the 4-carboxamido-quinazoline (QZ) scaffolds extensively investigated in our previously reported studies. Our attention was focused at position 4 of the phthalazine nucleus where different amido and ureido moieties were introduced (compounds [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Some of the new PHTZ compounds showed high hA 3 AR affinity and selectivity, the 2,5-dimethoxyphenylphthalazin-1(2H)-one 18 being the most potent and selective hA 3 AR antagonist among this series (K i = 0.776 nM; hA 1 / hA 3 and hA 2A /hA 3 > 12000).…”