Adenosine is a ubiquitous endogenous autacoid whose effects are triggered through the enrollment of four G protein-coupled receptors: A, A, A, and A. Due to the rapid generation of adenosine from cellular metabolism, and the widespread distribution of its receptor subtypes in almost all organs and tissues, this nucleoside induces a multitude of physiopathological effects, regulating central nervous, cardiovascular, peripheral, and immune systems. It is becoming clear that the expression patterns of adenosine receptors vary among cell types, lending weight to the idea that they may be both markers of pathologies and useful targets for novel drugs. This review offers an overview of current knowledge on adenosine receptors, including their characteristic structural features, molecular interactions and cellular functions, as well as their essential roles in pain, cancer, and neurodegenerative, inflammatory, and autoimmune diseases. Finally, we highlight the latest findings on molecules capable of targeting adenosine receptors and report which stage of drug development they have reached.

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The thermodynamic parameters (Delta G degrees, Delta H degrees, Delta S degrees) of the drug-receptor binding equilibrium derived from equilibrium constant measurements at different temperatures and van't Hoff plots are reviewed. The analysis 186 independent experiments performed on 136 ligands binding to 10 biological receptors and, for comparison, to DNA and to two different enzymes. Delta H degrees and Delta S degrees values correlate according to the regression equation Delta H degrees (kcal mol(-1)) = -9.5 + 278 Delta S degrees (kcal K-1 mol(-1)) with a coefficient of 0.981. The correlating equation is of the form Delta H degrees = beta Delta S degrees and is expected for a case of enthalpy-entropy compensation with a compensation temperature beta = 278 K. The Delta H-Delta S correlation is carefully examined in terms of transmission of the experimental errors and of the representativeness of the experimental sample utilized. The correlation can be considered a true physical constraint for which, in spite of the relatively wide intervals of Delta H degrees and Delta S degrees allowed, the drug-receptor dissociation constant, K-D, can never be smaller than some 10 pM. The physicochemical origin of the Delta H-Delta S compensation is probably related to an intrinsic property of the hydrogen bond, which is the main force determining the association of the participants (drug, receptor binding site, water) in the drug-receptor binding equilibrium

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The A adenosine receptor (A AR) subtype is a novel, promising therapeutic target for inflammatory diseases, such as rheumatoid arthritis (RA) and psoriasis, as well as liver cancer. A AR is coupled to inhibition of adenylyl cyclase and regulation of mitogen-activated protein kinase (MAPK) pathways, leading to modulation of transcription. Furthermore, A AR affects functions of almost all immune cells and the proliferation of cancer cells. Numerous A AR agonists, partial agonists, antagonists, and allosteric modulators have been reported, and their structure-activity relationships (SARs) have been studied culminating in the development of potent and selective molecules with drug-like characteristics. The efficacy of nucleoside agonists may be suppressed to produce antagonists, by structural modification of the ribose moiety. Diverse classes of heterocycles have been discovered as selective A AR blockers, although with large species differences. Thus, as a result of intense basic research efforts, the outlook for development of A AR modulators for human therapeutics is encouraging. Two prototypical selective agonists, N6-(3-Iodobenzyl)adenosine-5'-N-methyluronamide (IB-MECA; CF101) and 2-chloro-N6-(3-iodobenzyl)-adenosine-5'-N-methyluronamide (Cl-IB-MECA; CF102), have progressed to advanced clinical trials. They were found safe and well tolerated in all preclinical and human clinical studies and showed promising results, particularly in psoriasis and RA, where the A AR is both a promising therapeutic target and a biologically predictive marker, suggesting a personalized medicine approach. Targeting the A AR may pave the way for safe and efficacious treatments for patient populations affected by inflammatory diseases, cancer, and other conditions.

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