Molecular recognition at purine and pyrimidine nucleotide (P2) receptors

In comparison to other classes of cell surface receptors, the medicinal chemistry at P2X (ligand-gated ion channels) and P2Y (G protein-coupled) nucleotide receptors has been relatively slow to develop. Recent effort to design selective agonists and antagonists based on a combination of library screening, empirical modification of known ligands, and rational design have led to the introduction of potent antagonists of the P2X(1) (derivatives of pyridoxal phosphates and suramin), P2X(3) (A-317491), P2X(7) (derivatives of the isoquinoline KN-62), P2Y, (nucleotide analogues MRS 2179 and MRS 2279), P2Y, (thiouracil derivatives such as AR-C126313), and P2Y(12) (nucleotide/nucleoside analogues AR-C69931X and AZD6140) receptors. A variety of native agonist ligands (ATP, ADP, UTP, UDP, and UDP-glucose) are currently the subject of structural modification efforts to improve selectivity. MRS2365 is a selective agonist for P2Y, receptors. The dinucleotide INS 37217 potently activates the P2Y(2) receptor. UTP-gamma-S and UDP-beta-S are selective agonists for P2Y(2)/P2Y(4) and P2Y(6) receptors, respectively. The current knowledge of the structures of P2X and P2Y receptors, is derived mainly from mutagenesis studies. Site-directed mutagenesis has shown that ligand recognition in the human P2Y, receptor involves individual residues of both the TMs (3, 5, 6, and 7), as well as EL 2 and 3. The binding of the negatively-charged phosphate moiety is dependent on positively charged lysine and arginine residues near the exofacial side of TMs 3 and 7.