Pharmacology of Adenosine Receptors: The State of the Art

Abstract

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.

The effect of two selective A1‐receptor agonists and the bitopic ligand VCP746 on heart rate and regional vascular conductance in conscious rats

“…Vecchio et al () have recently shown that VCP746 is a high affinity and potent agonist of A 2B ‐receptors. However, the potent vasodilator and tachycardia effects of VCP746 observed in the present study were more consistent with an effect on A 2A ‐receptors (Alberti et al, ; Borea et al, ; Headrick, Ashton, Meyer, & Peart, ). As a consequence, we have evaluated the agonist effect of VCP746 on CRE‐mediated reporter gene responses in CHO‐K1 cells stably expressing either the human A 2A ‐receptor or the human A 2B ‐receptor (Figure ).…”

“…Adenosine is present in all cells in tightly regulated concentrations (Borea, Gessi, Merighi, Vincenzi, & Varani, ; Fredholm, Ijzerman, Jacobson, Linden, & Müller, ). It is released under a variety of physiological and pathophysiological conditions to facilitate protection and regeneration of tissues (Borea et al, ; Fredholm et al, ; Müller & Jacobson, ). Adenosine acts via four different GPCRs (A 1 , A 2A , A 2B , and A 3 ) to mediate its physiological effects.…”

“…A 1 ‐ and A 3 ‐receptors are Gi/o‐coupled and mediate responses primarily via inhibition of AC activity and/or inhibition of neurotransmitter release (Fredholm et al, ; Hill, May, Kellam, & Woolard, ; Müller & Jacobson, ). A 2A ‐ and A 2B ‐receptors are Gs‐coupled and mediate their effects primarily via stimulation of AC activity (Borea et al, ; Fredholm et al, ; Müller & Jacobson, ).…”

“…In the heart, adenosine A 1 ‐receptor activation results in negative inotropic, chronotropic, and dromotropic effects (Borea et al, ; Fenton & Dobson, ; Headrick, Peart, Reichelt, & Haseler, ). In addition, it has been shown that selective A 2A adenosine receptor agonists are potent vasodilators in the rat that reduce BP and induce marked increases in heart rate and plasma renin activity (Alberti et al, ).…”

“…A number of selective agonists and antagonists are now available for the A 1 ‐receptor (Borea et al, ; Fredholm et al, ; Müller & Jacobson, ). Some A 1 ‐receptor‐selective agonists and partial agonists have undergone evaluation for cardiovascular disease indications such as paroxysmal supraventricular tachycardia, atrial fibrillation, angina pectoris and heat failure (Meibom et al, ; Müller & Jacobson, ).…”