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 P2Y12 and P2X7 antagonist, as a result, we developed and tested a series of indole derivatives4a-lhaving 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 P2Y1, P2Y2, P2Y4 and P2Y6 receptors. Most of the compounds exhibited moderate to excellent inhibition activity against P2Y1 receptor subtype. The series most potent compound, 4h exhibited an IC50 value of 0.36 ± 0.01 µM selectivity against other subtypes of P2Y receptor. To investigate the ligand-receptor interactions, the molecular docking studies were carried out. Compound 4h is the most potent P2Y1 receptor antagonist due to interaction with an important amino acid residue Pro105, in addition to Ile108, Phe119, and Leu102.
Subject(s)
Indomethacin/pharmacology , Purinergic Antagonists/pharmacology , Receptors, Purinergic/metabolism , Thiourea/pharmacology , Cell Line, Tumor , Dose-Response Relationship, Drug , Humans , Indomethacin/chemical synthesis , Indomethacin/chemistry , Molecular Structure , Purinergic Antagonists/chemical synthesis , Purinergic Antagonists/chemistry , Structure-Activity Relationship , Thiourea/chemistryABSTRACT
A series of [5-substituted-4-phenyl-1,3-thiazol-2-yl] benzamide and furamide analogues were investigated in radioligand binding studies at adenosine receptor subtypes with an aim to obtain potent and selective adenosine receptor ligands. Benzamide and furamide linked to thiazole was found to be crucial for high adenosine receptor affinity. The most potent compound indentified in this study was 5d with low nanomolar affinity for all four adenosine receptor subtypes. Compounds 5a and 5g showed moderate selectivity for A2A adenosine receptors. Molecular docking versus all four human adenosine receptors combined with membrane molecular dynamics studies were performed to rationalise the peculiar selectivity profile of 5d antagonist.
Subject(s)
Benzamides/chemistry , Furans/chemistry , Purinergic Antagonists/chemistry , Receptors, Purinergic P1/metabolism , Thiazoles/chemistry , Adenosine A2 Receptor Antagonists/chemical synthesis , Adenosine A2 Receptor Antagonists/chemistry , Adenosine A2 Receptor Antagonists/pharmacology , Amides/chemical synthesis , Amides/chemistry , Amides/pharmacology , Animals , Benzamides/chemical synthesis , Benzamides/pharmacology , Binding Sites , Binding, Competitive , CHO Cells , Cricetinae , Cricetulus , Furans/chemical synthesis , Furans/pharmacology , Humans , Models, Chemical , Models, Molecular , Molecular Conformation , Molecular Structure , Protein Structure, Tertiary , Purinergic Antagonists/chemical synthesis , Purinergic Antagonists/pharmacology , Radioligand Assay , Receptor, Adenosine A2A/chemistry , Receptor, Adenosine A2A/genetics , Receptor, Adenosine A2A/metabolism , Receptors, Purinergic P1/chemistry , Receptors, Purinergic P1/genetics , TransfectionABSTRACT
A novel series of P2Y(12) antagonists for development of drugs within the antiplatelet area is presented. The synthesis of the piperazinyl-pyridine urea derivatives and their structure-activity relationships (SAR) are described. Several compounds showed P2Y(12) antagonistic activities in the sub-micromolar range.
