Adenosine antagonists xanthines

Another proposed mechanism is the inhibition of cell surface receptors for adenosine. These receptors modulate adenylyl cyclase activity, and adenosine has been shown to cause contraction of isolated airway smooth muscle and to provoke histamine release from airway mast cells. These effects are antagonized by theophylline, which blocks cell surface adenosine receptors. It has also been shown, however, that xanthine derivatives devoid of adenosine-antagonistic properties (eg, enprofylline) may be more potent than theophylline in inhibiting bronchoconstriction in asthmatic subjects. 

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. 

Xanthine bases or purine alkaloids are secondary metabolites, derivatives of xanthine caffeine, theophylline and theobromine are three very well-known examples. These compounds occur naturally in the seeds of coffee, cola, guarana and cacao, as well as in the leaves of tea and mate (Council of Europe, 1989 Zheng et al 2004). These compounds improve and stimulate blood circulation, an action that justifies the use of these vegetable compounds in anti-cellulite cosmetic formulations (Bertin et al 2001). Such an effect is the consequence of their adenosine-antagonist action, which influences the )S-adrenergic system by stimulating the vasodilator response. Additionally, xanthine bases specifically... 

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. 

Adenylate cyclase activity is modulated by the binding of free adenosine. The metnyP xanthines are antagonists to adenosine but their bindings do not produce its modulating N (inhibitory, attenuating) response. Therefore the end result is stimulatory in relation to J cAMP activity. 

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). 

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 BRONCHODILATORS -THEOPHYLLINE 1 efficacy of adenosine Theophylline and other xanthines are adenosine receptor antagonists Watch for poor response to adenosine higher doses may be required... 

M.A. Jacobson, P.K. Chakravarty, R.G. Johnson and R. Norton, Novel, selective, non-xanthine Aj adenosine receptor antagonists. Drug Devel. Res., 1996, 37,131. 

Selective C-arylation of free (AW)-purines via catalytic C-H bond functionalization has been developed <03JA5274>. Substitution at the 2 or 8 positions of 9-ethyladenine with a variety of side-chains was accomplished in order to obtain non-xanthine adenosine receptor antagonists... 

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