Adenosine receptor antagonism

Theophylline and aminophylline may produce bronchodilation by inhibition of phosphodiesterase (thereby increasing cyclic adenosine monophosphate levels), inhibition of calcium ion influx into smooth muscle, prostaglandin antagonism, stimulation of endogenous catecholamines, adenosine receptor antagonism, and inhibition of release of mediators from mast cells and leukocytes. 

Theophylline, a dimethylxanthine, causes broncho-dilation, possibly by inhibiting the enzyme phosphodiesterase in smooth muscle of the bronchioli. An other proposed mechanism of action is that of adenosine receptor antagonism. It has positive chronotropic and inotropic, CNS stimulant and weak diuretic properties. In obstructive lung disease sustained release tablets are to be preferred. Theophy-line has a narrow therapeutic index. Therapeutic plasma concentrations are between 7-15 mg/1. Theophylline undergoes N-demethylation via CYPl A2 in the liver and is eliminated in the urine as metabolites... 

Widely investigated as modulators of L-type calcium channels, several 1,4-dihydropyridines (e.g., Nifedipine, Fig. 7.2) proved also to bind A adenosine receptor in rat brain (Hu et al. 1987 Ismail et al. 1995). Considering the similarity between A, and A3 subtypes, Jacobson and co-workers exploited the 1,4-dihydropyridine nucleus as a template for probing SAR profde at A3 adenosine receptor. It was possible to separate the antagonism of L-type calcium channels from adenosine receptor antagonism, meanwhile enhancing A3 AR selectivity, through the introduction of... 

More recent studies provided evidence against a role for TGF in acute AmB nephrotoxicity. In contrast to its inhibition of TGF activity, theophylline prevented the acute renal responses to AmB by a mechanism unrelated to adenosine receptor antagonism [102]. Furthermore, micropuncture studies revealed that the AmB-induced reduction in single nephron GFR was the same irrespective of whether TGF was active or interrupted (by measuring GFR from distal and proximal tubular collections, respectively) [96]. The latter study also showed that distal tubular chloride ion concentrations were not increased by AmB, which indicated that the signal for TGF was unchanged. 

Heyne N, Wolf S, Petersen P, Merten S, Schober W, Erley CM, RislerT, Osswald FI. Adenosine receptor antagonism In the prevention of acute cyclosporine A- nephrotoxicity in normal, diabetic and hypertensive rats. Nephrol Dial Transplant 1999 14 SuppI 4 23-24. 

Persson, C.G.A. (1982). Universal adenosine receptor antagonism is neither necessary nor desirable with xanthine antiasthmatics. Med. Hypotheses 8, 515-526. 

In acute overdose, peak serum levels > 100 pg ml may be predictive of arrhythmias and seizures. The use of sustained-release formulations and the presence of pharmacobezors in the gut may make it difficult to determine peak serum levels. Sinus tachycardia is the most common cardiac sign of theophylline toxicity. Ventricular and supraventricular tachycardia, ectopic beats, hypotension, and cardiac arrest may occur. Metabolic acidosis, hypokalemia, hypercalcemia, and hyperglycemia may be seen. Tremulousness and agitation frequently occur. Intractable seizures may occur in severe intoxications, probably secondary to adenosine receptor antagonism in the brain. Onset of seizures is a poor prognostic indicator. Persistent vomiting is commonly seen and may interfere with attempts at therapy. 

Theophylline effectively relaxes airway smooth muscle this bronchodilation likely contributes to its acute therapeutic efficacy in asthma. Both adenosine receptor antagonism and PDE inhibition are likely involved in the bronchodilating effect of theophylline. Inhibition of PDE4 and PDE5 effectively relaxes human isolated bronchial smooth muscle, and inhibition of these PDEs likely contributes to the bronchodilating effect of theophylline. Studies with the related methylxanthine enprofylline (3-propylxanthine), which has been investigated extensively for treatment of asthma in Europe, also support a mechanistic role for PDE inhibition in the bronchodilator actions of theophylline. 

Inhibitors of phosphodiesterase increase the intracellular level of cyclic AMP, which is associated with increased myocardial contractility. One of the first POE-inhibitors so studied is theophylline (21), an important drug in the treatment of asthma. Its actions have been extensively reviewed.81 Several recent studies have indicated that it might stimulate contractility also by adenosine receptor antagonism.82 In patients with chronic obstructive pulmonary disease, theophylline (14 mg/kg, p.o.) improved cardiac performance.83,94 severe adverse side effects were observed.85,96 Many derivatives of theophylline and other purine analogs were prepared and tested as PDE-inhibitors and cardiac stimulants, some of them being several times more active than... 

Adenosine receptor antagonism appears to be the mechanism that explains most of the effects of caffeine on CNS activity, intestinal peristalsis, respiration, blood pressure, lipolysis, catecholamine release, and renin release. However, some effects, such as opiate antagonism or effects that... 

The xanthine family give rise to a number of natural products such as caffeine (1,3,7-trimethylxanthine). Caffeine pharmacology involves adenosine receptor antagonism but details remain elusive. The xanthine backbone forms the basis of a large number of derivatives acting as adenosine receptor antagonists. 

Three major mechanisms of action have dominated as possible explanations for the ergogenic potential of caffeine in the enhancement of exercise performance. These three mechanisms involve (1) the mobilization of intracellular calcium from the sarcoplasmic reticulum of skeletal muscle, (2) the increase of cyclic-3 ,5 -adenosine monophosphate (cAMP) by the inhibition of phosphodiesterases in muscles and adipocytes, and (3) the competitive antagonism of adenosine receptors, primarily in the central nervous system (CNS).8 9... 

Although caffeine is known to mobilize intracellular calcium, to inhibit phosphodiesterase activity, and to increase in vitro 5-HT and NE concentrations in the brainstem (Garrett and Griffiths 1997 Berkowitz et al. 1970 Carter et al. 1995 Solinas et al. 2002), it is now widely accepted that the mechanism of action of caffeine on wakefulness, at least at the dose range produced by voluntary caffeine intake, is via the antagonism of adenosine receptors. 

The chief direct mechanism of the methyixanthines is the antagonism of adenosine receptors (Snyder and Sklar 1984). Adenosine is an inhibitory neurotransmitter, acting at inhibitory presynaptic autoreceptors. At... 

Metabolism of adenosine is slowed by dipyridamole, indicating that in patients stabilized on dipyridamole the therapeutically effective dose of adenosine may have to be increased. Methylxanthines antagonize the effects of adenosine via blockade of the adenosine receptors. 

B. Methylxanthines have been proposed to be inhibitors of phosphodiesterase, which would elevate intracellular levels of cAMP. However, the concentration of cAMP that is required for such action is above the threshold of CNS stimulation. Since the methylxanthines are relatively potent antagonists of adenosine and since adenosine has been shown to be a reasonably potent inhibitor of both central and peripheral neurons, the most likely mechanism by which CNS stimulation occurs is through antagonism of adenosine receptors. 

Mecfianism of Action A methylxanthine and competitive inhibitor of phosphodiesterase that blocks antagonism of adenosine receptors. Therapeutic Effect Stimulates respiratory center, increases minute ventilation, decreases threshold of or increases response to hypercapnia, increases skeletal muscle tone, decreases diaphragmatic fatigue, increases metabolic rate, and increases oxygen consumption. Pharmacokinetics Protein binding 36%. Widely distributed through the tissues and CSF. Metabolized in liver. Excreted in urine. Half-life 3-7 hr. 

Competitive antagonism of adenosine receptors xanthines are potent inhibitors at adenosine receptors these may stimuiate or inhibit cAMP and Ca2+ influx. 

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. 

Sebastiao AM, Stone TW, Ribeiro JA (1990) The inhibitory adenosine receptor at the neuromuscular junction and hippocampus of the rat antagonism by 1,3,8-substituted xanthines. Br J Pharmacol 101 453-9... 

The drug of choice for most Americans is caffeine. In fact, caffeine is the most widely used psychoactive drug in the world. Many of caffeine s effects are believed to occur because of competitive antagonism at adenosine receptors. Adenosine is a neuromodulator that influences a number of functions in the CNS. The mild sedating... 

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