A3 32-Receptors

Neurotropic and antistress properties of 2,4-dimethylpyrido[l, 2-u]pyr-imidinium perchlorate were compared with those of piracetam (95MI7). AH-Pyrido[l,2-u]pyrimidin-4-one binds selectively to rat A3 receptors with a A", value of 48/xM. No affinities were observed to rat Ai and A2 receptors (96MI17). 4-Oxo-4//-pyrido[l,2-u]pyrimidine-3-carboxylic acid and -3-carbonitrile did not exhibit significant antibacterial activities (97MI6). 

Adenosine is produced by many tissues, mainly as a byproduct of ATP breakdown. It is released from neurons, glia and other cells, possibly through the operation of the membrane transport system. Its rate of production varies with the functional state of the tissue and it may play a role as an autocrine or paracrine mediator (e.g. controlling blood flow). The uptake of adenosine is blocked by dipyridamole, which has vasodilatory effects. The effects of adenosine are mediated by a group of G protein-coupled receptors (the Gi/o-coupled Ai- and A3 receptors, and the Gs-coupled A2a-/A2B receptors). Ai receptors can mediate vasoconstriction, block of cardiac atrioventricular conduction and reduction of force of contraction, bronchoconstriction, and inhibition of neurotransmitter release. A2 receptors mediate vasodilatation and are involved in the stimulation of nociceptive afferent neurons. A3 receptors mediate the release of mediators from mast cells. Methylxanthines (e.g. caffeine) function as antagonists of Ai and A2 receptors. Adenosine itself is used to terminate supraventricular tachycardia by intravenous bolus injection. 

Adenosine Receptors. Figure 1 Structures of widely used AR agonists, both nonselective and selective. Affinities/potencies at the ARs are found in Table 2. (a) Nucleoside derivatives that are either nonselective or selective for A receptors (1-12). (b) Nucleoside derivatives that are selective for A2a. A2a/A2b (mixed), or A3 receptors (13-19). 

While the findings in mice are of interest, it is important to note that there are four known mammalian adenosine receptors and that the pattern of adenosine receptor expression on mast cells (as well as other immime cells and/or structural cells), and the regulation of their expression by such cells (e.g., during inflammatory responses), which can represent major determinants of adenosine responses, vary substantially among species [70-72]. For example, it is thought that adenosine-induced broncho-constriction is mediated by adenosine A1 and A2B receptors in rats and mice, A3 receptors in rats, guinea-pigs and mice, and A2B receptors in humans [72]. 

Roller BH Adenosine and inosine increase cutane- 73 ous vasopermeability by activating A3 receptors on mast cells. J Clin Invest 2000 105 361-367. 74... 

In platelets, depletion of intracellular Ca + reduces 5-HT transport and this points to calmodulin as another endogenous regulator and its antagonists do inhibit 5-HT uptake. In contrast, activation of adenosine (A3) receptors seems to upregulate the transporter, possibly through the PKG, NO/cGGP pathway. 

Jacobsen, KA (1998) Adenosine A3 receptors novel ligands and paradoxical effects. Trends Pharmacol. Sci. 19 184-191. 

Van Muijlwijk-Koezen and co-workers utilized the reaction sequence beginning with the deprotonation of aminonitrile 139, which when trapped with various nitriles produced aminoquinazolines 140 upon acid-promoted cyclization, in their preparation of numerous aminoquinazoline as antagonists for the human adenosine A3 receptor <00JMC2227>. 

Chen Y, Corriden R, Inoue Y, Yip L, Hashiguchi N. Zinkernagel A, Nizet V. Insel PA. Junger WG ATP release guides neutrophil chemotaxis via P2Y2 and A3 receptors. Science 2006 314 1792-1795. 

A3 receptors. These are also known collectively as purine PI receptors. There are two other classes of purine receptors, P2X and P2Y, which are thought to be involved in nociception and especially visceral pain. The ligand for these receptors is ATP. The A1 receptor is coupled to the inhibitory Gi protein and the A2 receptor to the stimulatory Gs protein, and respectively inhibit or activate adenylyl cyclase, while the A3 receptor mediates G protein-dependent activation of phospholipase C. 

Today four subtypes of adenosine receptors - Ai, A2a, A2b and A3 - are known, all of which are members of the G-protein coupled receptor (GPCR) family. While A2a and A2b receptors stimulate adenylyl cyclase and consequently lead to an increase of cAMP levels, A1 and A3 receptors produce the opposite effect upon activation. 

There is some evidence that adenosine also participates in modulating peripheral somatosensory function through A3 receptors on immune cells. A predominant response to the activation of A3 receptors is degranulation of mast cells causing the release of multiple proinflammatory mediators (IL-6/IL-10/IL-12). Further involvement of A3 receptors in pain and inflammation may be a result of adenosine-mediated inhibition of the release of tumor necrosis factor a (TNF-a), a proinflammatory cytokine produced by monocytes and macrophages. 

From Hypertension (+) to Asthma Interactions with the Adenosine A3 Receptor from a Personal Perspective... 

The Hypotensive Response to A3 Receptor Ligands in the Rat Is Mast Cell Dependent... 

Adenosine facilitates preformed mediator and possibly cytokine release from mast cells by activating A3 receptors. 

Antagonists at the A3 receptor would prevent periodic exacerbations of asthma and lead over the longer term to a reduction in airways inflammation and bronchial hyperresponsiveness. 

With this brief, our chemistry colleagues set out to design antagonists with potency and selectivity at the A3 receptor and we biologists went off to devise mechanistic and/or disease models in which their molecules could be evaluated. 

The Design and Synthesis of Novel Potent and Selective A3 Receptor Antagonists... 

The Receptor Responsible for Adenosine Augmentation of Mediator Release from Human Mast Cells Is Not the A3 Receptor... 

At about the time that the efforts of the chemists to synthesise selective A3 antagonists had begun to bear fruit (1995/1996), the assumption implicit in our concept that human mast cells would behave like those of the rodent was called into serious question. The first (and key) observations came from Feoktistov and Biaggioni (1995) who provided evidence that in the human mast cell line, HMC-1 (which although derived from a patient with mast cell leukaemia shows some biochemical characteristics similar to the mast cells of the lung (Feoktistov et al. 1998)), the A2B receptor and not the A3 receptor is responsible for the potentiation of phorbol... 

The Design of Mixed A2B/A3 Receptor Antagonists and Their Biological Evaluation In Vitro... 

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