A novel class of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines as A3 adenosine receptor antagonists

Adenosine is an endogenous nucleoside distributed in several mammalian organisms’ tissues. It modulates different important physiological functions. Adenosine cannot be identified as a neurotransmitter because there is no clear evidence that it is stored in or released by specific purinergic nerves, so adenosine is usually considered a neuromodulator. It is well known that adenosine interacts with G-protein-coupled receptors that were classified in four receptors subtypes: A1, A2A, A2B, and A3 adenosine receptors (AR). A2A and A2B ARs stimulate adenylyl cyclase; instead, A1 and A3 ARs inhibit adenylyl cyclase. Moreover A1, A2B and A3 ARs stimulate also phospholypase C. Adenosine receptor antagonists have several potential therapeutic applications. In particular, A1 antagonists are diuretic. Through adenosine antagonist action towards A2A AR, we have a lot of CNS effects, such as neuroprotection, sleep disorder regulation and neurodegenerative disease treatment (Parkinson’s and Huntington’s diseases). A2B AR antagonists could be used in asthma and also as hypoglycemic. A3 antagonism is useful in glaucoma; moreover, due to the fact that A3 AR is widely expressed in some cancer cells, A3 AR antagonists could be used for tumoral diagnosis [1]. It was demonstrated by several studies that pyrazolo-triazolo-pyrimidine (PTP) core is a good template to obtain potent and selective adenosine receptor antagonists [2]. Our attention is focused on A3 ARs because up to now, phenylureidic and phenylacetamidic substitutions in position 5 are the only discovered A3 PTP antagonists where a carbonyl moiety is always present. So we synthesized a novel class of pyrazolo[4,3-e]1,2,4-triazolo[1,5-c]pyrimidines bearing an N8-methyl group and different amine moieties in position 5. This kind of derivatives could demonstrate that carbonyl moiety is not essential to have affinity towards A3 ARs