Recent developments in selective agonists and antagonists acting at purine and pyrimidine receptors

The SAR at adenosine (P 1 ) and ATP (P 2 ) receptors is reviewed, with emphasis on recently developed selective agonists and antagonists. These include partial (e.g., N 6 ‐ethyl‐8‐cyclopentylaminoadenosine) and full A 1 agonists (e.g., NNC 21‐0136, 2‐chloro‐N 6 ‐[(R)‐(benzothiazolylthio‐2‐propyl]adenosine), A 2 antagonists (e.g., the non‐xanthines: SCH58261, 5‐amino‐7‐(phenylethyl)‐2‐(2‐furyl)‐pyrazolo[4,3‐e]1,2,4‐triazolo[1,5‐c]pyrimidine and ZM241385, 4‐(2‐[7‐amino‐2‐(2‐furyl)[1,2,4]triazolo[2,3a][1,3,5]triazinyl‐amino]ethyl)‐phenol; and the 1‐propargyl‐8‐styrylxanthines), and A 3 agonists (e.g., Cl‐IB‐MECA, 2‐chloro‐N 6 ‐(3‐iodobenzyl)‐adenosine‐5′‐N‐methyluron‐amide). Novel adenosine receptor antagonists (e.g., BTH 4 , ethyl 3‐benzylthio‐4,5,6,7‐tetrahydro‐benzo[c]thiophen‐4‐one‐1‐carboxylate) have been discovered through screening libraries of natural products and heterocyclic derivatives. The first A 3 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 2 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 2 blocker, while a truncated derivative, NF023, appears to be selective for P2X receptors. More selective P 2 antagonists are under development, with the cloning of these receptors. [ 35 S]ATP‐γ‐S has been used as a radioligand for the direct labeling of several subtypes of cloned P2X receptors (P2X 1 ‐P2X 4 ). Drug Dev. Res. 39:289–300, 1996. © 1997 Wiley‐Liss, Inc. This is a US Government work and, as such, is in the public domain in the United States of America.