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Review
. 2016 Jul 27;21(8):974.
doi: 10.3390/molecules21080974.

Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks

João P Monteiro  1 , Marco G Alves  2 , Pedro F Oliveira  3   4 , Branca M Silva  5
Affiliations
Review

Structure-Bioactivity Relationships of Methylxanthines: Trying to Make Sense of All the Promises and the Drawbacks

João P Monteiro et al. Molecules. .

Abstract

Methylxanthines are a group of phytochemicals derived from the purine base xanthine and obtained from plant secondary metabolism. They are unobtrusively included in daily diet in common products as coffee, tea, energetic drinks, or chocolate. Caffeine is by far the most studied methylxanthine either in animal or epidemiologic studies. Theophylline and theobromine are other relevant methylxanthines also commonly available in the aforementioned sources. There are many disseminated myths about methylxanthines but there is increased scientific knowledge to discuss all the controversy and promise shown by these intriguing phytochemicals. In fact, many beneficial physiologic outcomes have been suggested for methylxanthines in areas as important and diverse as neurodegenerative and respiratory diseases, diabetes or cancer. However, there have always been toxicity concerns with methylxanthine (over)consumption and pharmacologic applications. Herein, we explore the structure-bioactivity relationships to bring light those enumerated effects. The potential shown by methylxanthines in such a wide range of conditions should substantiate many other scientific endeavors that may highlight their adequacy as adjuvant therapy agents and may contribute to the advent of functional foods. Newly designed targeted molecules based on methylxanthine structure may originate more specific and effective outcomes.

Keywords: caffeine; cancer; diabetes; methylxanthine; neurodegenerative diseases; structure-activity relationship; theobromine; theophylline.

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Conflict of interest statement

The authors declare that there are no conflicts of interest.

Figures

Figure 1
Figure 1
Chemical structures of the three major natural methylxanthines (caffeine, theophylline and theobromine) and paraxanthine.
Figure 2
Figure 2
Effects of the structural substitutions of the xanthine molecule on adenosine antagonism and systematic effects: 1. Substitution in position 1 is necessary for high affinity and selectivity towards adenosine receptor sites [116]. 2. Substitution in position 3 increases bronchodilator effect [117,118]. 3. Substitution in position 7 decreases both adenosine receptor antagonism and bronchodilator potency [116,117,119]. 4. Substitution in position 9 results in decreased adenosine receptor affinity [119,120]. 5. Substitution in position 8 increases adenosine antagonism and selectivity towards A1 receptors [116,121,122].
Figure 3
Figure 3
Main mechanisms proposed to mediate the pharmacological activity of methylxanthines at the cellular level.
See this image and copyright information in PMC

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