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. 1996 Nov-Dec;39(3-4):289-300.
doi: 10.1002/(sici)1098-2299(199611/12)39:3/4<289::aid-ddr8>3.0.co;2-n.

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

Kenneth A Jacobson  1 , Fumio Suzuki  2
Affiliations

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

Kenneth A Jacobson et al. Drug Dev Res. 1996 Nov-Dec.

Abstract

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).

Keywords: ATP; adenosine; agonists; antagonists; structure activity relationships; xanthines.

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Figures

Figure 1.
Figure 1.
Adenosine agonists (affinity at A1/A2A/A3 receptors in nM rat, except as indicated, h = human).
Figure 2.
Figure 2.
Adenosine antagonists (affinity at A1/A2A/A3 receptors in nM in rat, except as indicated, h = human, s = sheep, gp = guinea pig).
Figure 3.
Figure 3.
P2 receptor agonists (K0.5 in nM for activation of turkey P2Y1 receptors is shown).
Figure 4.
Figure 4.
P2 receptor antagonists.
See this image and copyright information in PMC

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