Forskning

May 22, 2020

A2A adenosine receptor antagonists: from caffeine to selective non-xanthines

K A Jacobson et al, 2020. A2A adenosine receptor antagonists: from caffeine to selective non-xanthines, British Journal of Pharmacology, published online.

ABSTRACT:

A long evolution of knowledge of the psychostimulant caffeine, led in the 1960s to another purine natural product, adenosine and its A_2A adenosine receptor (A_2A AR). Adenosine is a short-lived autocrine/paracrine mediator that acts pharmacologically at four ARs in a manner opposite to 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. A_2A AR inhibition is one of caffeine’s principal targets, and we now understand this interaction at the atomic level. The A_2A AR has become a prototypical example of utilizing high-resolution structures of G protein-coupled receptors (GPCRs) for the rational design of chemically diverse drug molecules. The previous focus on selective A_2A AR antagonist discovery for neurodegenerative diseases has expanded to include immunotherapy for cancer, and clinical trials have ensued.