The Medicinal Chemistry of Caffeine

Abstract

The purine alkaloid caffeine is the most widely consumed psychostimulant drug in the world and has multiple beneficial pharmacological activities, for example, in neurodegenerative diseases. However, despite being an extensively studied bioactive natural product, the mechanistic understanding of caffeine’s pharmacological effects is incomplete. While several molecular targets of caffeine such as adenosine receptors and phosphodiesterases have been known for decades and inspired numerous medicinal chemistry programs, new protein interactions of the xanthine are continuously discovered providing potentially improved pharmacological understanding and a molecular basis for future medicinal chemistry. In this Perspective, we gather knowledge on the confirmed protein interactions, structure activity relationship, and chemical biology of caffeine on well-known and upcoming targets. The diversity of caffeine’s molecular activities on receptors and enzymes, many of which are abundant in the CNS, indicates a complex interplay of several mechanisms contributing to neuroprotective effects and highlights new targets as attractive subjects for drug discovery.

The Conflicting Role of Caffeine Supplementation on Hyperoxia-Induced Injury on the Cerebellar Granular Cell Neurogenesis of Newborn Rats

“…One of the standard drugs most commonly used in neonatal care for the treatment of apnea in preterm infants is the methylxanthine caffeine. As a nonspecific inhibitor of adenosine receptor subtypes A1 and A2a, caffeine has a broad spectrum of pharmacokinetic activity [ 38 , 39 ]. In addition to reducing the frequency of respiratory arrest, caffeine showed well-described short- and long-term effects [ 40 ].…”

Updated Prediction of Aggregators and Assay Interfering Substructures in Food Compounds

“…A large research effort is being devoted to the determination of the biological mechanism of action of food compounds, in order to understand the beneficial or harmful effect of foods in human health. [1][2][3][4][5][6][7][8][9]44 These studies are conducted by performing biochemical or biological (cellular) assays aiming to see if the food molecule interacts with some biological target, typically a protein. It is well known from the field of drug discovery that in some cases an assay can result in a false positive or misleading outcome due to some property of the tested molecule: 10,24,[26][27][28]41 the molecule forms colloidal aggregates that denature the target protein or has some substructure that make it prone to membrane disruption, (photo)reactivity, redox cycling, etc., or rather to generate interferences with the assay signal.…”

“…There is currently a great research effort in the identification of the biological mechanisms of action of food compounds from a molecular point of view, in order to understand the beneficial or harmful effects of foods on human health, as well as finding novel nutraceuticals and scaffolds for drug design. [1][2][3][4][5][6][7][8][9] For that aim, biochemical and/or biological (cellular) assays directed towards different biological targets (typically proteins) are being conducted, so that specific macromolecule-food compound interactions can be identified. However, these assays are subject to compound-related artifacts.…”

A Sulfonated Tweezer-Shaped Receptor Selectively Recognizes Caffeine in Water

“… 3 Caffeine also plays multiple roles as a drug for its antibronchospastic properties and is used as an analgesic adjuvant for pain treatment. 4 Other attractive effects of caffeine have been observed in the prevention of neurodegenerative diseases and cancer immunotherapy. 5 The use of artificial receptors that effectively recognize caffeine in water can therefore find a wide range of applications in biomedical, technological, and analytical fields.…”