Xanthines agonists

Improvements in asthma treatment include the development of more effective, safer formulations of known dmgs. The aerosol adrninistration of P2-agonists or corticosteroids results in a decrease in side effects. Also, the use of reUable sustained release formulations has revolutionized the use of oral xanthines which have a very narrow therapeutic index (see Controlled release technology). For many individuals, asthma symptoms tend to worsen at night and the inhaled bronchodilatots do not usually last through an entire night s sleep (26,27). 

The structure activity relationships ( SAR) of newly synthesized analogues of nucleosides, xanthine heterocycles, and nonxanthine heterocycles have been explored at the ARs. Potent and selective AR antagonists have been prepared for all four subtypes [3, 4], and selective agonists are known for three subtypes [1]. Thus, numerous pharmacological tools are available for in vitro and in vivo use (Table 2). Potent and selective A2b AR agonists are yet to be repotted, although several research groups have identified lead compounds. 

A xanthine series (I) exemplified by 33 and 34 is another important class of GPR109A agonists [83-88], It is worth noting that members of this series lack the carboxylic acid to interact with Arglll of GPR109A, unlike compounds in the aforementioned series. However, it is conceivable that the N-H present in the bicyclic core of this class of compounds is sufficiently acidic (pKa 5.6) [82] to mimic the function of a carboxylic acid present in the anthranilide class. 

Fusion of a barbituric acid motif and a pyrone ring afforded compounds containing a novel pyranopyrimidine core (L) that were discovered as GPR109A agonists [92,93]. This core appears to be distinct from other fused bicyclic cores such as xanthine and anthranilide based on their poor overlap. Furthermore, several compounds, exemplified by 39 and 40, provided remarkable potency in the cAMP assay. The critical acidic functional group is present as the N-PI of barbituric acid motif which has a calculated pKa of 8 [82]. 

Apparently related to the aforementioned xanthine analogs, pyridopyrimidinone (X =X2=X3=CH or CR) and aza-pyridopyrimidinone (X1 or X3=N, X2=CH or CR) derivatives (M), exemplified by compounds 41 and 42 respectively, were discovered as GPR109A agonists [94,95]. So far no biological data has been provided for this class of molecules. The calculated pKa of the N-H group present in compounds 41 and 42 ranges from 8 to 9 [82]. 

Furukawa, C. T. (1988). Comparative trials including a beta 2 adrenergic agonist, a methyl-xanthine, and a mast cell stabilizer. Ann. Allergy 60,472-476. 

Metaproterenol (Alupent, Metaprel) [Bronchodilator/ Beta-Adrenergic Agonist] Uses Asthma reversible bronchospasm Action Sympathomimetic bronchodilator Dose Adults. Neb 0.2-0.3 mL in 2.5-3.0 mL of NS Peds. Neb 0.1-0.2 mL/kg of a 5% soln in 2.5 mL NS Caution [C, /-] Contra Tach, other arrhythmias Disp Aerosol 0.65 mg/inhal soln for inhal 0.4, 0.6% tabs 10, 20 mg syrup 10 mg/5 mL SE Nervousness, tremors (common), tach, HTN Interactions T Effects W/ sympathomimetic drugs, xanthines T risk of arrhythmias W/ cardiac glycosides, halothane, levodopa, theophylline, thyroid hormones T HTN W/ MAOIs effects W/ BBs EMS Separate additional aerosol use by 5 min fewer 3i effects than isoproterenol longer-acting monitor lung sounds before/after administration... 

SEs Paradoxical bronchospasm, URI, pharyngitis, back pain Interactions T Effects WTadrenergics T effects OF BBs T risk of hypokalemia W/ corticosteroids, diuretics, xanthines T risk of aiihytlimias W/ MAOIs, TCAs EMS Not for acute asthma, use an inhaled 3-agonist attacks may affect glucose (hyperglycemia) use caution w/ nonselective BBs, may cause severe bronchospasm diuretic use may cause hypokalemia, monitor ECG for signs (flattened T waves) OD May cause profound P-stimulation a cardioselective BB may be useful... 

EUkena D, Jacobson KA, Padgett WL, Ayala C, Shamin MT, Kirk KL, Olsson RA, Daly JW, Species differences in structure-activity relationships of adenosine agonists and xanthine antagonists at brain Al adenosine receptors FEBS Lett. 209, 122-128, 1986. 

Adenosine, in addition to serving as a substrate for the generation of cAMP plays a physiologic role as a platelet inhibitor and a vasodilator and may attenuate neutrophil-mediated damage to endothelial cells, Adenosine diphosphate (ADP)— a potent platelet agonist—is converted to adenosine, which is taken up rapidly by cells, especially erythrocytes and endothelial cells, A small proportion is metabolized to the aforementioned cyclic nucleotides. The remainder is broken down to inosine and subsequently to xanthine. Dipyridamole inhibits the active transport of adenosine into cells, but does not interfere with the passive diffusion. Since the platelet inhibitory effects of adenosine proceed via stimulation of adenylate cyclase, these effects can also be amplified by dipyridamole, In circulating blood, the largest amount of adenosine is found in red blood cells, This may, in part, help explain why dipyridamole is much more effective in whole blood than in plasma. 

In 1987 the xanthine derivative theophylline was the most commonly used medication in the treatment of asthma, followed by / 2-agonists, such as albuterol or ter-butaline, and inhaled corticosteroids, for example budesonide or flunisolide. Today, the most frequently used medication is inhaled / 2-agonists and it is expected that these therapy patterns have shifted toward greater use of inhaled corticosteroids [4, 5], Nevertheless, whether used alone or in combination with other therapies, corticosteroids do not consistently abrogate airway inflammation in patients with asthma common side effects associated with this type of drug are increased heart rate, nervousness, tremors, nasal irritation, nausea, and headaches [8, 10, 11],... 

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