Xanthine derivatives Theobromine Theophylline

The three methalated xanthine derivatives (methyixanthines) theophylline, theobromine, and caffeine are plant alkaloids. Theophylline is the only one of these which is widely used therapeutically. Three possible modes of action have been proposed ... 

Xanthine derivatives are a group of chemically similar compounds that exert a variety of pharmacologic effects. Common xanthine derivatives include theophylline, caffeine, and theobromine (Fig. 26-2) these compounds are frequently found in various foods and beverages (tea, coffee, soft drinks). Theophylline and several theophylline derivatives are also administered therapeutically to produce bronchodilation in asthma and other forms of reversible airway obstruction (bronchitis, emphysema).65,79 Theophylline and caffeine are also potent CNS stimulants, and some of the more common side effects of these drugs are related to this CNS excitation (see Adverse Side Effects, later in this chapter). 

The major bases found in nucleic acids are adenine and guanine (purines) and uracil, cytosine, and thymine (pyrimidines). Thymine is found primarily in DNA, uracil in RNA, and the others in both DNA and RNA. Their structures, along with their chemical parent compounds, purine and pyrimidine, are shown in Figure 10.1, which also indicates other biologically important purines that are not components of nucleic acids. Hypoxanthine, orotic acid, and xanthine are biosynthetic and/or degradation intermediates of purine and pyrimidine bases, whereas xanthine derivatives—caffeine, theophylline, and theobromine—are alkaloids from plant sources. Caffeine is a component of coffee beans and tea, and its effects on metabolism are mentioned in Chapter 16. Theophylline is found in tea and is used therapeutically in asthma, because it is a smooth muscle relaxant. Theobromine is found in chocolate. It is a diuretic, heart stimulant, and vasodilator. 

A series of xanthine derivatives including theophylline, cafleine, theobromine and pentoxifylline (Fig. 12.15) that have bronchcxUlator properties have been shown to be non-selective phosphodiesterase inhibitors. 

Ultraviolet spectroscopy is used in many clinical laboratories due to its ease of operation and availability. A classical method for theophylline determination in plasma is the one of Schack and Waxier.45 The original method had interferences from phenobarbitol and various xanthine derivatives such as theobromine.46 The modification of the method by Jatlow47 eliminated the interferences from barbituates but included the various... 

Contraindications History of intolerance to xanthine derivatives, such as caffeine, theophylline, or theobromine recent cerebral or retinal hemorrhage... 

Caffeine (melting point 238°C, sublimes at 178°C density 1.23), theobromine, and theophylline are xanthine derivatives classified as central nervous stimulants, but differing markedly in their properties. They can be extracted from a number of natural sources. 

The naturally occurring purines fall into 4 main groups. (1) Simple substituted derivatives of purine (1) such as adenine (2) and various 6-AT-substituted derivatives. (2) Monoxo-dihydropurines such as hypoxanthine (3), guanine (4), and isoguanine (5). f3) Dioxotetra-hydropurines such as xanthine (6) and methylated derivatives including the 3,7-dimethyl derivative theobromine (7), 1,3-dimethylxanthine or theophylline f8), and 1,3,7-trimethylxanthine or caffeine (9). (4) Trioxohexahydropurines such as uric acid (10). 

The purine group of alkaloids includes the vegetable alkaloids caffeine, theobromine, theophylline and the animal alkaloids xanthine, hypoxanthine, guanine and adenine. The most common substance which is a purine compound is uric acid, but, though directly related to the alkaloids given above, it is not itself usually considered as an alkaloid. The constitution of uric acid has been fully considered (Part I, p. 442). It is the tri-hydroxy derivative of a substance known as purine which is the mother substance of the purine alkaloids also. 

Several authors have included one or more naturally occurring xanthine derivatives (caffeine, theobromine and theophylline) in their gas chromatographic separation of alkaloids. Lloyd et al.1 used a packed column with SE-30 on Chromosorb VI, so did Brochmann-Hanssen and... 

The first systematic investigation on the gas chromatographic separation of xanthine de-rivatives was published by Reisch and Walker. The naturally occurring xanthines, caffeine, theobromine and theophylline, as well as a number of derivatives, were gas chromatographed on an 1.5 % packed SE-30 column on Chromosorb W. In Table 20.1 the compounds are given and and in Figure 20.1 typical gas chromatograms. 

Fig. 11.1. Separation of some xanthine derivatives Column pBondapak C18 (300x4 rim ID), mobile phase acetonitrile - 0.01 M sodium acetate buffer (pH 4.0) (7 93), flow rate 2.0 ml/min, detection UV 254 nm. Peaks 1, 1-methyluric acid 2, 3-methyl xanthine 3, 1,3-dimethyl-uric acid 4, theobromine 5, theophylline 6, B-hydroxy-ethyltheophylline 7, phenobarbital 8, caffeine 9, 8--chlorotheophyl1ine. (reproduced with permission from ref. 56, by the courtesy of Clinical Chemistry)...

XANTHINE-DERIVATIVES (see N06) Theobromine has a stronger diuretic effect than caffeine and theophylline (R03D). 

NO6B C Xanthine derivatives The drugs included in the following table all have varying contents of the xanthinederivatives theophylline, theobromine and caffeine. 

Brominelammonia. Expose the chromatogram to bromine vapor for 2 minutes, hold it in the steam from a boiling water bath for 1 minute, then heat in the oven at 110°-120° for 5 minutes. With caffeine, theobromine, theophylline and other xanthine derivatives a rose pink spot develops which becomes reddish purple when exposed to ammonia. 

Experiments with liver slices and cultured cell lines have corroborated this pathway of purine degradation. In human liver slices 16 xanthine derivatives were produced from caffeine by action of P-450 system. Demethylation at N-3 was the most prominent process [18, 19]. Comparison of cell lines from humans, hamsters, mice, and rats show some interspecies differences but all of them demethylated and oxidized caffeine [20]. Human liver cells give 1,3,7-trimethylurate as the major metabolite of caffeine, but also made were the intermediate products theobromine, theophylline, and paraxanthine [21]. Human liver microsomes convert theophylline to 1-methylxanthine, 3-methylxanthine, and 1,3-dimethyluric acid [22, 23]. Human kidney microsomes produced each of the three possible demethylated products as well as 1,3,7-... 

Caffeine shows slight central neuron excitatory action, accelerates the depressed center function, increases activity generally, and improves the depressive state. The basic purine skeleton in which the 2 and 6 positions became carbonyl groups, as occurs in caffeine, theobromine, and theophylline, is called a xanthine. Therefore, these alkaloids are also known as xanthine derivatives. 

Similar to polyphenols, alkaloids are products of the secondary metabolism of plants, which have been identified in hundreds of plant species with great structural diversity [21], Methybcanthines derived from purine nucleotides are known collectively as purine alkaloids. Caffeine, theophylline, and theobromine alkaloids are methylated xanthine derivatives. Figure 14.2 shows their chemical structures and, as can be observed, these structures differ only in the number and the position of one methyl substituent and/or hydrogen atom around the xanthine ring system. 

Purine alkaloids are methyl derivatives of xanthine. The most common purine alkaloid is 1,3,5-trimethykanthine, 1,3,7-trimethyl-lH-purine-2,6(3H,7H)-dione, known trivially as caffeine (10-38). It is accompanied by dimethykanthines theobromine, theophylline and paraxanthine and also by methykanthine heteroxanthine and methyluric acids, which are minority alkaloids, with the exception of cocoa and chocolate. Caffeine is found in the seeds, leaves and fruits of more than 60 species of plants. It is assumed that the purpose of accumulation of purine alkaloids by plants is the protection... 

First, their water solubility clearly increases according to the series xanthine, theobromine, theophylline, and caffeine. Curiously, the most methylated derivative is the most soluble and the least methylated one the least soluble. Second, no regularity is found in the melting-point values of these derivatives. The explanation of these anomalies lies, at least in part, in the formation of hydrogen bonds. In caffeine, the... 

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

Foods derived from cocoa beans have been consumed by humans since at least 460 to 480 AD. The source of cocoa beans, the species Theobroma, contains a variety of biologically active components. These include the purine alkaloids theobromine, caffeine, and theophylline. Structurally, they are methylated xanthines and, thus, are often referred to as methylxanthines. Theobromine (3, 7-dimethylxanthine) is the predominant purine alkaloid in cocoa and chocolate. Caffeine (1, 3, 7-trimethylxanthine), the major purine alkaloid found in coffee and tea, is found in cocoa and chocolate at about one eighth the concentration of theobromine. Only trace amounts of theophylline (1, 3-dimethylxanthine) are detected in cocoa and chocolate products. 

Three xanthines are pharmacologically important caffeine, theophylline, and theobromine. All three alkaloids, which occur naturally in certain plants, are widely consumed in the form of beverages (infusions or decoctions) derived from these plants. Coffee primarily contains caffeine (about 100-150 mg per average cup) tea contains caffeine (30-40 mg per cup) and theophylline and cocoa contains caffeine (15-18 mg per cup) and theobromine. Cola drinks also contain significant amounts of caffeine (about 40 mg/12 oz). The CNS stimulation associated with these beverages is predominantly due to the caffeine. 

Several purine derivatives are found in nature, e.g. xanthine, hypoxanthine and uric acid. The pharmacologically important (CNS-stimulant) xanthine alkaloids, e.g. caffeine, theobromine and theophylline, are found in tea leaves, coffee beans and coco. The actual biosynthesis of purines involves construction of a pyrimidine ring onto a pre-formed imidazole system. 

The purine alkaloids caffeine, theobromine, and theophylline (Figure 6.135) are all methyl derivatives of xanthine and they commonly co-occur in a particular plant. The major sources of these compounds are the beverage materials such as tea, coffee, cocoa, and cola, which owe their stimulant properties to these water-soluble alkaloids. They competitively inhibit phosphodiesterase, resulting in an increase in cyclic AMP and subsequent release of adrenaline. This leads to a stimulation of the CNS, a relaxation of bronchial smooth muscle, and induction of diuresis, as major effects. These effects vary in the three compounds. Caffeine is the best CNS stimulant, and has weak diuretic action. Theobromine has little stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine. 

Methyl derivatives of xanthine (2,3-dioxypurine) namely caffeine (1,3,7-trimethyl-xanthine), theobromine (3,7-dimethylxanthine) and theophylline (1,3-dimethylxanthine) (Section 1, Appendix) are variously found in plants used for stimulatory drinks such as Ilex paraguayensis (mate) (Aquifoliaceae), Coffea species (coffee) (Rubiaceae), Paullinia cupana (guarana) (Sapindaceae), Cola acuminata (cola) and Theabroma cacao (cocoa) (Sterculiaceae) and Camellia sinensis (tea) (Theaceae). These methylxanthines are variously active as inhibitors of... 

The prototypical structural class of nonselective PDE inhibitors is represented by the methylxanthines (Figure 9.4), a family of plant-derived alkaloids that includes theophylline (1), caffeine (2), and theobromine (3) [9], Although limited in potency, these simple naturally occurring xanthines were the parents in the later discoveries of more potent synthetic derivatives such as pentoxyfylline (4) and isobutylmethyl-xanthine (IBMX, 5). In particular, the latter compound has been widely used and has been regarded for decades as the gold standard nonselective inhibitor of all PDEs. Only recently has it become clear that some of the newer PDEs (8 and 9) are not inhibited by IBMX. Derivatives of IBMX carrying substituents at the 8 position confer increased potency [10], An example is compound 6, which retains most of... 

Other key derivatives, xanthine (2,6-dihydroxypurine, 4) and hypoxanthine (6-hydroxypurine, 5), are formed by the hydrolytic decomposition of nucleic acids. As their systematic names indicate, the well-known CNS stimulants caffeine (1,3,7-trimethylxanthine, 6), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethyl-xanthine), found in coffee, tea, and cocoa beans, respectively, are all derived from xanthine. 

Caffeine, theobromine, and theophylline are purine derivatives closely related to the xanthine bodies found in the urine and tissues of animals. Xanthine is 2 6 dioxypurine caffeine is 1 3 7 trimethylxanthine theobromine is 3 7 di-methylxanthine and theophylline is 1 3 dimethylxanthine. They aU resemble each other in most points of their pharmacological action, but they differ markedly in the relative intensity of their action on various functions. Thus, caffeine is the most potent CNS stimulant of the group theobromine... 

Caffeine enters the bloodstream about ten minutes after its ingestion and stays in the body for up to twelve hours. Like other alkaloids, caffeine has powerful physiological effects on humans and animals. It stimulates heart muscle and relaxes certain structures that contain smooth muscle, including the coronary arteries and the bronchi. It is a diuretic. Theophylline and theobromine, two other plant alkaloid derivatives of xanthine, have physiological effects similar to those of caffeine. 

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