Adenosine receptors methylxanthines

Our observations suggest that [ H]chloroadenosine, an adenosine receptor agonist, identifies binding sites in human placenta with characteristics of the high affinity, adenosine receptor. The binding is time dependent, reversible and saturable. The potency series of adenosine receptor methylxanthine antagonists in displacing C Hi chloroadenosine is appropriate. 

The often severe headaches, common in caffeine withdrawal, appear to be caused by vasodilation of cerebral blood vessels. This action is probably mediated by the action of the methylxanthines on adenosine receptors. 

Rail, T. W., Evolution of the mechanism of action of methylxanthines From calcium mobilizers to antagonists of adenosine receptors, Pharmacologist, 24, 277, 1982. 

The generic name of the cacao tree (Theobroma) means food of the Gods and gives its name to a caffeine-like stimulant, theobromine (a methylxanthine). It has been claimed that the theobromine in chocolate is responsible for its addictive characteristics. This is based on the fact that methylxanthines bind to adenosine receptors in the central nervous system and act as antagonists to this neurotransmitter (Chapter 14). However, another group of substances, the amides formed between ethanolamine and unsaturated fatty acids, are also possible candidates for the title of the chocolate drug . 

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. 

The methylxanthines have positive chronotropic and inotropic effects. At low concentrations, these effects appear to result from inhibition of presynaptic adenosine receptors in sympathetic nerves increasing catecholamine release at nerve endings. The higher concentrations (more than 10 i mol/L, 2 mg/L) associated with inhibition of phosphodiesterase and increases in cAMP may result in increased influx of calcium. At much higher concentrations (more than 100 mol/L), sequestration of calcium by the sarcoplasmic reticulum is impaired. 

Mechanism of action The methylxanthines may act by several mechanisms, including translocation of extracellular calcium, increase in cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) caused by inhibition of phosphodiesterase, and blockade of adenosine receptors. 

Adenosine binds to adenosine receptors (AD-Rs) (subtypes Ah A2A, A2b and A3). Ap and Ap R activation gives Gai-mediated inhibition of adenylyl cyclase (resulting in decreased cAMP) and Gai/Gao-mediated activation of a K+ channel (with a de-excitatory hyperpolarizing effect). A2A and A2B activation gives Gas-mediated stimulation of adenylate cyclase (resulting in elevated cAMP). Adenosine acting via particular receptors variously has cardioprotective, neuroprotective, sedative, anticonvulsant, soporific, vasodilatory and bronchoconstrictive effects. The plant-derived methylxanthines theophylline and caffeine are adenosine A1 and A2 receptor antagonists (Table 5.1). 

Theophylline, a methylxanthine, relaxes bronchial muscle, although its precise mode of action is still debated. Inhibition of phosphodiesterase (PDE), especially its type 4 isoform now seems the most likely explanation for its bronchodilator and more recently reported anti-inflammatory effects. Blockade of adenosine receptors is probably unimportant. Other actions of theophylline include chronotropic and inotropic effects on the heart and a direct effect on the rate of urine production (diuresis). 

The CNS-stimulating effects of the methylxanthines were once attributed to their phosphodiesterase-inhibiting ability. This action is probably irrelevant at therapeutic doses. Evidence indicates that the overall CNS-stimulant action is related more to the ability of these compounds to antagonize adenosine at A and A a receptors. All of the roles of these receptors are still under study. The adenosine receptor subtypes and their pharmacology have been reviewed. -Problems with (he present compounds, such as caffeine and theophylline, are lack of receptor selectivity and (he ubiquitous nature of the various receptor subtypes. 

Cafleine, theobromine and theophylline, and related methylxanthine compounds, are mild stimulants and have everyday use, e.g. in tea. coffee, chocolate and some soft drinks. Methylxanthines work in part as PHOSPHODIESTERASE INHIBITORS and in part as antagonists at P,-purinoceptors (see ADENOSINE RECEPTOR ANTAGONISTS). 

Some other drugs that appear to owe part of their action to phosphodiesterase inhibition include a number of naturally occurring methylxanthine drugs and their derivatives (e.g. aminophylline. caffeine, theobromine, theophylline), but they also have ADENOSINE RECEPTOR ANTAGONIST properties see BRONCHODILATORS CENTRAL STIMULANTS. 

The effects of adenosine are potentiated in patients receiving dipyridamole, an adenosine-uptake inhibitor, and in patients with cardiac transplants owing to denervation hypersensitivity. Methylxanthines, such as theophylline and caffeine, block adenosine receptors therefore, larger than usual doses are required to produce an antiarrhythmic effect in patients who have consumed these agents in beverages or as 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. 

B. Mechanism of Action The methylxanthines inhibit phosphodiesterase (PDE), the enzyme that degrades cAMP to AMP (Figure 20-3), and thus increase cAMP. This anti-PDF effect, however, requires high concentrations of the drug. Methylxanthines also block adenosine receptors in the CNS and elsewhere, but a relationship between this action and the bronchodilat-ing effect has not been clearly established. It is possible that bronchodilation is caused by a third tis yet unrecognized action. 

Caffeine is one of a group of substances called methylxanthines. They are closely similar compounds to adenine and guanine, which are building blocks in the nucleotides AMP, ADP, ATP and GMP, GDP and GTP. Caffeine is the main stimulant substance in coffee but similar compounds, theophylline and theobromine, are found in cocoa and tea. All of them promote wakefulness. Caffeine is the stimulant in such drinks as Red Bull. One of the sites of action of these substances is the enzyme cAMP phosphodiesterase, where they act as inhibitors (see Appendix 13). This effectively keeps the systems that are activated by cAMP switched on. It is now known also that these compounds have another site of action in the brain and elsewhere. In these locations there are inhibitory adenosine receptors, upon which caffeine acts as an antagonist. 

J.W. Daly, R.F. Bruns, and S.H. Snyder, Adenosine receptors in the central nervous system relationship to the central actions of methylxanthines. Life Sciences 28 2083 (1981). 

There are several targets for the methylxanthines in the human body. The most common two are phosphodiesterase enzyme inhibition and adenosine receptor inhibition. 

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. 

Reeves JJ, Jones CA, Sheehan MJ, Vardey CJ, Whelan CJ (1997) Adenosine A3 receptors promote degranulation of rat mast cells both in vitro and in vivo. Inflamm Res 46(5) 180-184 Ribeiro JA, Walker J (1975) The effects of adenosine triphosphate and adenosine diphosphate on transmission at the rat and frog neuromuscular junctions. Br J Pharmacol 54(2) 213-218 Ribeiro JA, Sebastiao AM (1984) Enhancement of tetrodotoxin-induced axonal blockade by adenosine, adenosine analogues, dibutyryl cyclic AMP and methylxanthines in the frog sciatic nerve. Br J Pharmacol 83(2) 485—492... 

---