Abstract
G-protein-coupled receptors for extracellular nucleotides are known as P2Y receptors and are made up of eight members that are encoded by distinct genes and can be classified into two classes based on their affinity for specific G-proteins. P2Y receptor modulators have been studied extensively, but only a few small-molecule P2Y receptor antagonists have been discovered so far and approved by drug agencies. Derivatives of indole carboxamide have been identified as P2Y(12) and P2X(7) antagonist, as a result, we developed and tested a series of indole derivatives 4a-l having thiourea moiety as P2Y receptor antagonist by using a fluorescence-based assay to measure the inhibition of intracellular calcium release in 1321N1 astrocytoma cells that had been stably transfected with the P2Y(1), P2Y(2), P2Y(4) and P2Y(6) receptors. Most of the compounds exhibited moderate to excellent inhibition activity against P2Y(1) receptor subtype. The series most potent compound, 4h exhibited an IC50 value of 0.36 +/- 0.01 mu M selectivity against other subtypes of P2Y receptor. To investigate the ligandreceptor interactions, the molecular docking studies were carried out. Compound 4h is the most potent P2Y(1) receptor antagonist due to interaction with an important amino acid residue Pro105, in addition to Ile108, Phe119, and Leu102.