Adenosine A2Areceptor antagonists: from caffeine to selective non-xanthines

A long evolution of knowledge of the psychostimulant caffeine led in the 1960s to another purine natural product, adenosine and its A(2A)receptor. Adenosine is a short-lived autocrine/paracrine mediator that acts pharmacologically at four different adenosine receptors in a manner opposite to the pan-antagonist caffeine and serves as an endogenous allostatic regulator. Although detrimental in the developing brain, caffeine appears to be cerebroprotective in aging. Moderate caffeine consumption in adults, except in pregnancy, may also provide benefit in pain, diabetes, and kidney and liver disorders. Inhibition of A(2A)receptors is one of caffeine's principal effects and we now understand this interaction at the atomic level. The A(2A)receptor has become a prototypical example of utilizing high-resolution structures of GPCRs for the rational design of chemically diverse drug molecules. The previous focus on discovery of selective A(2A)receptor antagonists for neurodegenerative diseases has expanded to include immunotherapy for cancer, and clinical trials have ensued.

Automated summary

Caffeine and adenosine, along with their interaction with the A(2A) receptor, play crucial roles in the brain, particularly in the protection of aging brain and potential treatments for various diseases. Understanding the atomic-level interaction with the A(2A) receptor has led to the development of diverse drug molecules. The focus has expanded from neurodegenerative diseases to include cancer immunotherapy.