Recent Developments in Selective Agonists and Antagonists Acting at Purine and Pyrimidine Receptors

The SAR at adenosine (P) and ATP (P) receptors is reviewed, with emphasis on recently developed selective agonists and antagonists. These include partial (e.g., N-ethyl-8-cyclopentylaminoadenosine) and full A agonists (e.g., NNC 21-0136, 2-chloro-N-[()-(benzothiazolylthio-2-propyl]adenosine), A antagonists (e.g., the non-xanthines: SCH58261, 5-amino-7-(phenylethyl)-2-(2-furyl)-pyrazolo[4,3-]1,2,4-triazolo[1,5-]pyrimidine and ZM241385, 4-(2-[7-amino-2-(2-furyl)[1,2,4]triazolo[2,3][1,3,5]triazinyl-amino]ethyl)-phenol; and the 1-propargyl-8-styrylxanthines), and A agonists (e.g., CI-IB-MECA, 2-chloro-N-(3-iodobenzyl)-adenosine-5'-N-methyluron-amide). Novel adenosine receptor antagonists (e.g., BTH, ethyl 3-benzylthio-4,5,6,7-tetrahydro-benzo[]thiophen-4-one-1-carboxylate) have been discovered through screening libraries of natural products and heterocyclic derivatives. The first A selective antagonists to be identified include derivatives of flavones (MRS 1067), 1,4-dihydropyridines (MRS 1097), triazolonaphthyridine (L-249313), and thiazolopyrimidine (L-268605). Potent P receptor agonists are known. For example, 2-HexylthioAMP is a highly potent agonist at the yet uncloned P2Y receptor in C6 glioma cells. Suramin is a weak and non-selective P blocker, while a truncated derivative, NF023, appears to be selective for P2X receptors. More selective P antagonists are under development, with the cloning of these receptors. [S]ATP-γS has been used as a radioligand for the direct labeling of several subtypes of cloned P2X receptors (P2X-P2X).