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

The SAR at adenosine (P₁) and ATP (P₂) receptors is reviewed, with emphasis on recently developed selective agonists and antagonists. These include partial (e.g., N⁶-ethyl-8-cyclopentylaminoadenosine) and full A₁ agonists (e.g., NNC 21-0136, 2-chloro-N⁶-[(R)-(benzothiazolylthio-2-propyl]adenosine), A₂ 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 A₃ agonists (e.g., CI-IB-MECA, 2-chloro-N⁶-(3-iodobenzyl)-adenosine-5'-N-methyluron-amide). Novel adenosine receptor antagonists (e.g., BTH₄, 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 A₃ selective antagonists to be identified include derivatives of flavones (MRS 1067), 1,4-dihydropyridines (MRS 1097), triazolonaphthyridine (L-249313), and thiazolopyrimidine (L-268605). Potent P₂ 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 P₂ blocker, while a truncated derivative, NF023, appears to be selective for P2X receptors. More selective P₂ antagonists are under development, with the cloning of these receptors. [³⁵S]ATP-γS has been used as a radioligand for the direct labeling of several subtypes of cloned P2X receptors (P2X₁-P2X₄).