Adenosine receptors binding sites

Exploring distal regions of the A3 adenosine receptor binding site sterically-con-strained iV< -(2-phenylethyl)adenosine derivatives as potent ligands. Bioorg Med Chem 12(9) 2021-2034... 

Moro S, van Rhee AM, Sanders LH, Jacobson KA. Flavonoid derivatives as adenosine receptor antagonists a comparison of the hypothetical receptor binding site based on a comparative molecular field analysis model. J Med Chem 1998 41(l) 46-52. 

FIGURE 4.18 Affinity of adenosine receptor agonists in whole cells (dark bars) and membranes (cross-hatched bars, high-affinity binding site). Data shown for (1) 2-phenylaminoadenosine, (2) 2-chloro adenosine, (3) 5 -N-ethylcarboxamidoadenosine, (4) N6-cyclohexyladenosine, (5) (-)-(R)-N6-phenylisopropyladenosine, and (6) N6-cyclopentyladenosine. Data redrawn from [15],... 

The P-site of adenylyl cyclase inhibits cyclic AMP accumulation. Since P, and P2 receptors are located on the cell surface, they bind purines or pyrimidines in the extracellular space. There also is an adenosine binding site located intracellularly on the enzyme adenylyl cyclase (see Ch. 21). This is referred to as the P-site of adenylyl cyclase. Binding of adenosine and other purines, notably 3 AMP, 2 deoxy-3 -ATP and 2, 5 -dideoxyadenosine to this site, inhibits adenylyl cyclase activity [8]. The P-site of adenylyl cyclase and other intracellular purine binding sites are not classified as purinergic receptors. 

The activation of adenylyl cyclase enables it to catalyze the conversion of adenosine triphosphate (ATP) to 3 5 -cyclic adenosine monophosphate (cAMP), which in turn can activate a number of enzymes known as kinases. Each kinase phosphorylates a specific protein or proteins. Such phosphorylation reactions are known to be involved in the opening of some calcium channels as well as in the activation of other enzymes. In this system, the receptor is in the membrane with its binding site on the outer surface. The G protein is totally within the membrane while the adenylyl cyclase is within the membrane but projects into the interior of the cell. The cAMP is generated within the cell (see Rgure 10.4). 

Rivkees, S. A., Barbhaiya, H., IJzerman, A. P. Identification of the adenine binding site of the human A1 adenosine receptor, J. Biol. Chem. 1999, 274, 3617-3621. 

In line with expression of A3 adenosine receptors in cells and tissues like mast cells, spleen and thymus putative binding sites for a number of transcription factors relevant for protein expression in inflammation and infection were identified in the promoter region of the A3 receptor gene (Atkinson et al. 1997 Zhao et al. 1999). These include activator protein 1 (AP-1) which regulates gene expression in response to viral and bacterial infections or to stimulation by cytokines. Additional binding sites for transcription factors with specificity for immune cells are for the T cell-specific T cell factor F-2-a (TcF-2-a) and for the B cell-specific E2aECB. 

Neoceptors have so far been applied successfully to the A3AR and to other ARs (Gao et al. 2006, Jacobson and Gao 2006 Jacobson et al. 2005). Structural modification of the ribose moiety, which binds in a hydrophilic region of the putative ligand binding site of the receptor, has been region of adenosine that is most suited for modification for neoceptor recognition. It was predicted previously in various... 

Cunha RA, Johansson B, Constantino MD, Sebastiao AM, Fredholm BB (1996a) Evidence for high-affinity binding sites for the adenosine A2A receptor agonist [3H] CGS 21680 in the rat hippocampus and cerebral cortex that are different from striatal A2A receptors. Naunyn Schmiedebergs Arch Pharmacol 353(3) 261-271 Cunha RA, Vizi ES, Ribeiro JA, Sebastiao AM (1996b) Preferential release of ATP and its extracellular catabolism as a source of adenosine upon high- but not low-frequency stimulation of rat hippocampal slices. J Neurochem 67(5) 2180—2187 de Mendonca A, Sebastiao AM, Ribeiro JA (1995) Inhibition of NMDA receptor-mediated currents in isolated rat hippocampal neurones by adenosine A1 receptor activation. Neuroreport 6(8) 1097-1100... 

Oliveira JC, Sebastiao AM, Ribeiro JA (1991) Solubilized rat brain adenosine receptors have two high-affinity binding sites for l,3-dipropyl-8-cyclopentylxanthine. J Neurochem 57(4) 1165—1171 Palmer TM, Benovic JL, Stiles GL (1995) Agonist-dependent phosphorylation and desensitization of the rat A3 adenosine receptor. Evidence for a G-protein-coupled receptor kinase-mediated mechanism. J Biol Chem 270(49) 29607-29613... 

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