Adenosine xanthine-derived

J. Leppanen, J. Huuskonen, J. Savolainen, T. Nevalainen, H. Taipale, J. Vepsalainen, J. Gynther, T. Jarvinen, Synthesis of a Water-Soluble Prodrug of Entacapone , Bioorg. Med. Chem. Lett. 2000, 10, 1967-1969 R. Sauer, J. Maurinsh, U. Reith, F. Ftille, K. N. Klotz, C. E. Muller, Water-Soluble Phosphate Prodrugs of l-Propargyl-8-styryl-xanthine Derivatives, A2A-Selective Adenosine Receptor Antagonists , J. Med. Chem. 2000, 43, 440-448. 

Another proposed mechanism is inhibition of cell-surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to provoke contraction of isolated airway smooth muscle and histamine release from airway mast cells. It has been shown, however, that xanthine derivatives devoid of adenosine antagonism (eg, enprofylline) may be potent in inhibiting bronchoconstriction in asthmatic subjects. 

Natural antagonists for ARs, such as caffeine and theophylline show in general low affinity for the A3 AR subtype (Baraldi et al. 2003). In a recent work, the approach based on the annelation of xanthine derivatives for the development of adenosine receptors antagonists has been extensively considered (Drabczy ska et al. 2003). 

Clarke H, Cushley MJ, Persson CG, Holgate ST (1989) The protective effects of intravenous theophylline and enprofylline against histamine- and adenosine 50-monophosphate-provoked bronchoconstriction implications for the mechanisms of action of xanthine derivatives in asthma. Pulm Pharmacol 2(3) 147-154... 

As adenosine antagonists, a great number of 8-substituted xanthines with varying substitution patterns in the 1- and 3-position have been prepared. As starting materials, l,3-dialkyl-5,6-di-aminouracils are used, which are transformed to the 1,3,8-trisubstituted xanthines by one of three methods. The first consists of condensing diaminouracil with an aldehyde to form the imine which is oxidatively cyclized by treatment with diethyl azodicarboxylate (DEAD) in a modification of a reported general procedureto give the appropriate xanthine derivative, e.g. formation of 10. 

DPCPX (PD 116948) is a xanthine derivative, a (PI purinoceptor) ADENOSINE RECEPTOR ANTAGONIST selective for... 

I Propentofylline, a xanthine derivative, protects against cell damage by increasing extracellular adenosine. This reduces the damaging activation of microgha Preliminary results promising. 

Purine itself simply forms an N -halogen complex, but does not undergo C-substitution, however adenosine, hypoxanthine and xanthine derivatives ° undergo fluorination, chlorination and bromination at C-8. However, there is the possibility that these substitution products arise via A-halo-purinium salts, nucleophilic addition of bromide anion to these at C-8, then elimination of hydrogen halide. 

Dyphylline is a xanthine derivative related to theophylline. It relaxes bronchial smooth muscle and stimulates central respiratory drive. It is indicated in the relief of acute bronchial asthma and reversible bronchospasm associated with chronic bronchitis and emphysema. A large number of derivatives of the methylxanthines have been prepared and examined for their ability to inhibit cyclic nucleotide phosphodiesterases (PDFs) and antagonize receptor-mediated actions of adenosine, the two best characterized cellular actions of the methylxanthines. Although certain modifications dissociate these two activities to some degree, these compounds are not used therapeutically. 

As activation of substance P and adenosine receptors produce the same effect (e.g., hypotension and an gesia), it was of therapeutic interest to combine these properties in a single compound. A xanthine derivative, an Aj adenosine receptor antagonist, was linked with the pentapeptide terminal part of substance P to give a twin drug (Fig. 16.26) with similar magnitude for both receptors. ... 

It appears that xanthine derivatives such as caffeine and theophylline might antagonise some of the haemodynamic effects of dipyridamole because they act as competitive antagonists of adenosine (an endogenous vasodilator involved in the action of dipyridamole). Due to these opposing effects, parenteral aminophylline has been used to treat adverse events associated with intravenous dipyridamole, - and it is recommended that aminophylline should be made available before beginning dipyridamole echocardiography. ... 

Mortola JP. Breathing pattern in newborns. J Appl Physiol 1984 56 1533-1540. Damall RA, Bmce RD. Effects of adenosine and xanthine derivatives on breathing during acute hypoxia in the anesthetized newborn piglet. Pediatr Pulmonol 1987 3 110-116. 

Because of the limited solubility of the xanthine derivatives in water, their solubilization by hydrotropes has been the subject of much interest. Such diverse compounds as piperazine [279], sodium salicylate [280], adenosine [281], and diethanolamine [282] have been used to solubilize theophylline. The action of each is presumably due to complex formation. Neish [283] found that caffeine, a xanthine derivative, increased the solubility of a number of aromatic amines, including sulphapyridine, sulphathiazole, and certain dyes. 

Other calorimetric studies [22] on human blood platelets were performed in order to clarify the mechanism of action of xanthine derivatives in relation to adenosine receptor. In addition, there were investigations on the effect of adenosine and adenosine agonists on platelet metabolism. The results showed that the two xanthine derivatives tested, enprofylline and theophylline, at therapeutic concentrations, did not modify the heat production induced by adenosine. Both adenosine and one adenosine agonist, NECA (5-N-ethyl carboxamide adenosine) increased platelet metabolism. The other adenosine agonist tested, PIA (L-N -phenylisopropyl-adenosine) induced a reduction of heat production. The adenosine uptake inhibitor, dipyridamol, was without effect. Thus, by microcalorimetry, useful information could be obtained concerning the complex mechanisms behind the effects on human cell metabolism of adenosine and adenosine agonists. The same applies to substances used in the treatment of asthma, xanthine derivatives they are thought to act by inhibition of adenosine receptors. 

In the most important degradative pathway for adenosine monophosphate (AMP), it is the nucleotide that deaminated, and inosine monophosphate (IMP) arises. In the same way as in GMP, the purine base hypoxanthine is released from IMP. A single enzyme, xanthine oxidase [3], then both converts hypoxanthine into xanthine and xanthine into uric acid. An 0X0 group is introduced into the substrate in each of these reaction steps. The oxo group is derived from molecular oxygen another reaction product is hydrogen peroxide (H2O2), which is toxic and has to be removed by peroxidases. 

As indicated in Fig. 25-18, free adenine released from catabolism of nucleic acids can be deaminated hydrolytically to hypoxanthine, and guanine can be deaminated to xanthine.328 The molybdenum-containing xanthine oxidase (Chapter 16) oxidizes hypoxanthine to xanthine and the latter on to uric acid. Some Clostridia convert purine or hypoxanthine to xanthine by the action of a selenium-containing purine hydroxylase.3283 Another reaction of xanthine occurring in some plants is conversion to the trimethylated derivative caffeine. 328b One of the physiological effects of caffeine in animals is inhibition of pyrimidine synthesis.329 However, the effect most sought by coffee drinkers may be an increase in blood pressure caused by occupancy of adenosine receptors by caffeine.330... 

---