Caffeine and Related Compounds

Seven chlorogenic and hydroxycinnamic acids (caffeic, p- and o-coumeric, ferulic, 4-methoxy-, 3,4-dimethoxy-, 3,4,5-trimethoxycinnamic) were extracted from green coffee and baseline resolved on a Cjg colunm (A = 320 nm) using a complex 47-min 15/85 - 80/20 methanol/water (1% acetic acid) gradient [374]. Peak shapes were excellent. Linear ranges of 4—400 pg/mL with detection limits of 0.1 pg/mL were reported. 

Methyluric acids are common decomposition products of methylxanthines such as caffeine. Five such compounds (I- and 7-melhyluric acid, 1,7- and 13-dimethyl-uric acid, and 1,3,7-trimethyluric acid) were extracted from urine and sqjarated on a Cj column (A = 280nm). A two-ramp 95/5— 80/20 (at 8 min)- 70/30 (at 15 min) water (acetate pH 3.5)/methanol gradient generated excellent separation and peak shapes [375]. The linear range was 25 pg/mL to 3 mg/mL with reported detection limits of lOng/mL. 

Five caffeine metabolites (5-acetylamino-6-fbmiylamino-3-methyluracil, 1-methyl- and 1,7-dimethylxanthine, 1-methyl- and 1,7-dimethyluric acid) were extracted from urine and separated on a C g column (A = 280nm). In addition, nine other related compounds (e.g., 3- and 7-methyhiric acid, 3- and 7-methyl-xanthine, and 1,3,7-trimethylxanthine) were also studied with these compounds using a 12/1/87 methanol/acetonitrile/water (0.05% acetic acid) mobile phase [376]. Concentration ranges of 4-100 pM were used. Peak shapes were very good and most peaks were well resolved. Elution was complete in 35 min. 

Caffeine and 14 metabolites (e.g., paraxanthine, 5-acetylamino-6-amino-3-methyluracil, dimethyluric acids, methybtanthines, and methyluric acids) were extracted from urine and separated on a Cig column (A = 280 nm) using a 45-min 92.5/7.5 -V 60/40 water (0.05% acetic acid)/methanol gradient [377]. Linear ranges were reported as 0.5-20 pg/mL with detection limits of 2ng/mL. 

Nine xanthines (xanthine, I-, 7-, and 3-methylxanthine, isocaffeine [IS], theobromine, paraxanthine, theophylline, caffeine) were extracted from serum and urine separated on a 32°C Cg column (A = 270 run) using a 20-min 90/10 70/30 water 

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Rousseau, E., LaDine, J., Liu, Q.-Y., Meissner, G. (1988). Activation of the Ca release channel of skeletal muscle sarcoplasmic reticulum by caffeine and related compounds. Arch. Biochem. Biophys. 267, 75-86. 

A book dealing with alkaloids in foods contains an account on caffeine and related compounds. The synthesis of caffeine, the conversion of uric acid into xanthine, and various syntheses of related heterocyclic compounds form subject matters in a review of broad scope. The role of purine alkaloids in trace-metal metabolism, disease resistance, mutagenesis, and chemotaxonomic considerations in plants has been reviewed. 

Table 9. Electrochemical oxidation of caffeine and related compounds (MeCN, Et3N 3HF) (94TL9237)...

Lean MEJ, Ashihara H, Clifford MN, Crozier A (2011) Purine alkaloids a focus on caffeine and related compounds in beverages. In Crozier A, Ashihara H, Tomas-Barberan F (eds) Teas, cocoa and coffee plant secondary metabolites and health. Wiley-Blackwell, Oxford, pp25 ... 

Dipyridamole and related compounds, RA233, RA433, VK744, VK774, caffeine, papaverine, aminophylline, theophylline, methylxanthines. 

Many drugs used for recreational as well as medical purposes can stimulate the central nervous system and so are referred to as stimulants. We separate. stimulants into tsvo groups according to their legal and social status. Controlled stimulants such as cocaine, amphetamines, methylphenidate (Ritalin), and related compounds are treated in this chapter, and over-the-counter stimulants such as nicotine and caffeine are dealt with in Chapters 7 and 8. We first consider the hi.story of stimulant use and discuss some of the effects of cocaine and the amphetamines as we review their history. Then we turn to a more detailed treatment of the pharmacology of these stimulants. 

Even some or most of the common garden vegetables and fruits contain trace amounts of alkaloids as well as other potentially beneficial types of compounds. Our daily cups of coffee contain the alkaloid caffeine. Tobacco and some other plants contain the alkaloid nicotine, and there is ongoing research to determine beneficial medicinal properties for nicotine and related compounds, possibly even against cancer. The alkaloid colchicine is sometimes used as a treatment for gout, although it is a drug also used in horticulture to induce mutations in plant species. 

Last but not least, it was also shown that fiubendiamide and its sulfoxide are specihc to insect ryanodine receptors and do not affect mammalian ryanodine receptors. Even high concentrations of fiubendiamide sulfoxide applied on differentiated mouse muscle C2C12 cells which express the muscle Subtype 1 and Subtype 111 did not either elicit Ca signals nor did they prevent the Ca transients elicited by caffeine (Figure 9). Therefore, we conclude that fiubendiamide and related compounds do not affect mammalian RyR Type I and III. These observations provide a good explanation for the excellent toxicological profile observed in the case of fiubendiamide. 

Commonly used drugs, dietary constituents and food additives may be electroactive and consequently are potential sources of interference when biological samples are analysed. Quinine may originate from tonic water, for example, caffeine from coffee and cafifeinated soft drinks and some proprietary stimulants, nicotine and cotinine from tobacco smoke, chloroquine and related compounds from malaria prophylaxis, and pholcodine and other opiate analogues from cold cures. Many such compounds and their metabolites will show an EC response at carbon electrodes under appropriate conditions and can be sources of confusion if unrecognised. 

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). 

Caffeine (1.10), found in coffee (Coffea arabica), was introduced to Europe through Constantinople (modem Istanbul) in the 1500s (Figure 1.5). The stimulant effects of coffee were widely acknowledged, but coffee was recognized as a useful diuretic. Caffeine was first synthesized by Emil Fischer in 1882. Two related compounds, theobromine (1.11) and theophylline (1.12), found in cacao seeds (Theobroma cacao) and tea (Camellia sinensi), respectively, are more potent diuretics than caffeine.1 All three compounds are based on the purine ring system (1.13). 

In most studies, the selectivities of the MIPs have been estimated by measuring the amount of each ligand required to displace 50% of the binding of radiolabelled imprint species to the MIP (IC50). The first MIA study reported excellent selectivity of the theophylline method for theophylline (1,3-dimethylxanthine) in the presence of the structurally related compound caffeine (1,3,7-trimethylxanthine) [3]. Despite their close resemblance (they differ by only one methyl group), caffeine showed less than 1 % cross-reactivity. A similar level of specificity was recorded for cortisol and corticosterone MIPs, which were able to detect the absence and presence of single hydroxyl groups and double bonds in the steroid structure [13]. 

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. 

Astrup A, Breum L, Toubro S, Hein P, Quaade F. The effect and safety of an ephedrine/caffeine compound compared to ephedrine, caffeine and placebo in obese subjects on an energy restricted diet a double blind trial. Int J Obes Relat Metab Disord 1992 16(4) 269-277. 

Caffeine is an alkaloid classified as a methylxanthine, a group of closely related compounds including caffeine, theophylline, and theobromine, that have similar physiological effects. Caffeine is the most widely consumed... 

The first example, depicted in Fig. 6, describes the synthesis and evaluation of a polymer imprinted with the bronchodilating drug theophylline, which is used in the treatment of asthma. Originally published in the journal Nature [2], this work drew considerable attention to the field of molecular imprinting because it was the first study to show that an MIP could be substituted for a natural antibody in a standard clinical assay. The MIP and antibody-based assays exhibit similar selectivities, and both can discriminate between theophylline and structurally related compounds. An equilibrium binding assay is described which uses radiolabeled theophylline as a marker. Data are presented for which nonradioactive theophylline, caffeine, and theobromine are used in competitive binding assays. These assays provide valuable information about the capacity and selectivity of the MIP. 

This approach has been used to imprint theophylline [74], which was attached to the surface of silica gel particles and an imprinted polymer assembled around the inorganic particles. When polymerization was complete, the silica was dissolved away with hydrofluoric acid. This yielded imprinted polymer particles with a narrow pore size distribution with diameters between 254 and 257 A compared with conventionally prepared imprinted polymers which have pore diameters in the range 30-1000 A. The imprinted polymer showed a high selectivity for theophylline over the related compounds caffeine and theobromine. 

Since the initial demonstration of the principle using theophylline and diazepam [16], organic-phase MIAs based on traditional MIPs have been developed for a number of other drugs and medical targets including morphine [21,37], Leu-enkephalin [37], cortisol and cortisone [42], yohimbine [43], caffeine [27,31,44], and bupivacaine [48]. In each case selectivity over related compounds has been demonstrated, and limits of detection are typically in the 100 nM to 1 pM range. Most of these studies were not optimized, but a thorough study was made of an MIA for S -propranolol and the detection limit lowered to 5.5 nM [38]. 

The parent compound, coumarin, has been found to cause chromosome breakage in animal tissues [207, 336]. The mechanism of this action and the effect on chromosomes by chemical mutagens has not yet been elucidated [337], There is hardly any structural relationship of action between these compounds. Good chromosome breakers of mammalian cells or plants include bromouracil, caffein and derivatives, alkylating agents, phenols, quinones, colchicine, methyl-phenyl-nitrosamine [337-343]. However, there is another plant product, podophyl-lotoxin, related to coumarin, which also causes chemical mutagenesis [338, 344]. 

Related findings were reported by Eisen and his collaborators, who showed that mouse myeloma protein, MOPC 315, which has anti-Dnp activity, also combines weakly with 5-acetyluracil, caffeine, and riboflavin, and somewhat more strongly with menadione (2-methyl-1,4-naphthaquinone) (105). None of these compounds is closely related structurally to the dinitrophenyl group. Cross-reactions with 5-acetyluracil of anti-Dnp antibodies induced in some but not all rabbits and guinea pigs were also observed (106). 

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