A(3) Adenosine receptors (ARs) exhibit large species differences. Potent, selective agonists for rat (e.g. Cl-IB-MECA, 5) and human A(3) ARs (e.g. PENECA, 17, and analogs) have been developed during the past years. Potent, selective antagonists for human A(3) ARs include the imidazopurinones PSB-10 (28) and PSB-11 (29), the pyrazolotriazolopyrimidines MRE-3005F20 (38) and analogs, and the dihydropyridines (e.g. MRS-1334, 50). For rat A(3) ARs only moderately potent antagonists have been identified, such as the pyridine derivative MRS-1523 (51) and the flavonoid MRS-1067 (52), both of which exhibit only a low degree of selectivity versus the other AR subtypes. Selective antagonist radioligands for the human A(3) receptor, [(3)H]MRE-3008F20 and [(3)H]PSB-11, have been prepared, while A(3)-selective agonist radioligands are still lacking. Recent developments also include allosteric modulators, irreversibly binding antagonists, fluorescence-labelled agonists, partial agonists and inverse agonists for A(3)ARs. Site-directed mutagenesis and molecular modeling studies have been performed in order to obtain information about the ligand binding site and the process of receptor activation. A(3)Adenosine receptors have recently attracted considerable interest as novel drug targets. A(3) Agonists may have potential as cardioprotective and cerebroprotective agents, for the treatment of asthma, as antiinflammatory and immunosuppressive agents, and in cancer therapy as cytostatics and chemoprotective compounds. A(3) AR antagonists might be therapeutically useful for the acute treatment of stroke, for glaucoma, and also as antiasthmatic and antiallergic drugs, since A(3)receptors cannot only mediate antiinflammatory, but also proinflammatory responses. The future development of further pharmacological tools, including potent, selective antagonists for rat A(3) receptors and selective agonist radioligands for rat and human receptors will facilitate the evaluation of the (patho)physiological roles of A(3) receptors and the pharmacological potential of their ligands.

01 Sep 1997·NeuropharmacologyQ2 · MEDICINE

Pharmacological characterization of novel A3 adenosine receptor-selective antagonists

Q2 · MEDICINE

Article

Author: Olah, Mark E. ; Jiang, Ji-Long ; Stiles, Gary L. ; Jacobson, Kenneth A. ; Park, Kyung-Sun ; Kim, Yong-Chul ; Ji, Xiao-Duo

The effects of putative A3 adenosine receptor antagonists of three diverse chemical classes (the flavonoid MRS 1067, the 6-phenyl-1,4-dihydropyridines MRS 1097 and MRS 1191, and the triazoloquinazoline MRS 1220) were characterized in receptor binding and functional assays. MRS1067, MRS 1191 and MRS 1220 were found to be competitive in saturation binding studies using the agonist radioligand [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)adenosine-5'-N-methyluronamide) at cloned human brain A3 receptors expressed in HEK-293 cells. Antagonism was demonstrated in functional assays consisting of agonist-induced inhibition of adenylate cyclase and the stimulation of binding of [35S]guanosine 5'-O-(3-thiotriphosphate) ([35S]GTP-gamma-S) to the associated G-proteins. MRS 1220 and MRS 1191, with KB values of 1.7 and 92 nM, respectively, proved to be highly selective for human A3 receptor vs human A1 receptor-mediated effects on adenylate cyclase. In addition, MRS 1220 reversed the effect of A3 agonist-elicited inhibition of tumor necrosis factor-alpha formation in the human macrophage U-937 cell line, with an IC50 value of 0.3 microM.

01 Nov 1996·Drug Development Research

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

Article

Author: Kenneth A. Jacobson ; Fumio Suzuki

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).

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Inflammation	Discovery	US	National Institutes of Health	-

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