Abstract
A new series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidine (PTP) derivatives has been developed in order to explore their affinity and selectivity profile at the four adenosine receptor subtypes. In particular, the PTP scaffold was conjugated at the C2 position with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole, a group believed to confer potency and selectivity toward the human (h) A2B adenosine receptor (AR) to the xanthine ligand 8-(1-(3-(trifluoromethyl)benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl-1H-purine-2,6(3H,7H)-dione (CVT 6975). Interestingly, the synthesized compounds turned out to be inactive at the hA2B AR but they displayed affinity at the hA3 AR in the nanomolar range. The best compound of the series (6) shows both high affinity (hA3 AR Ki = 11 nM) and selectivity (A1/A3 and A2A/A3 > 9090; A2B/A3 > 909) at the hA3 AR. To better rationalize these results, a molecular docking study on the four AR subtypes was performed for all the synthesized compounds. In addition, CTV 6975 and two close analogues have been subjected to the same molecular docking protocol to investigate the role of the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole on the binding at the four ARs.
Highlights
Adenosine is an ubiquitous modulator, which exerts its functions through interaction with four G protein-coupled receptors classified as A1, A2A, A2B and A3 adenosine receptors (ARs). [1,2] While A1, A2A and A3 ARs are stimulated by low concentrations of adenosine, the A2BPLOS ONE | DOI:10.1371/journal.pone.0143504 December 1, 2015
We have presented a novel series of pyrazolo[4,3-e][1,2,4]triazolo[1,5-c]pyrimidines bearing a 1-(3-trifluoromethyl-benzyl)1H-pyrazol-4-yl moiety at the C2 position in order to explore the effect on affinity and selectivity profiles at the four ARs
The 1-(3-trifluoromethylbenzyl)1H-pyrazol-4-yl group when attached at the 8 position of xanthine derivatives, such as CVT-6975 (1), is known to confer high affinity for the hA2B AR
Summary
Adenosine is an ubiquitous modulator, which exerts its functions through interaction with four G protein-coupled receptors classified as A1, A2A, A2B and A3 adenosine receptors (ARs). [1,2] While A1, A2A and A3 ARs are stimulated by low concentrations of adenosine, the A2B. [22] In the non-xanthine family, some adenine [23], 7-deazapurines [24], triazolo-triazine, [24] quinazoline, [25], triazinobenzimidazole [26], pyrimidine [27] and pyrazine [28] derivatives have been reported as hA2B AR antagonists, but few of the synthesized compounds (e.g. pyrimidines) showed both significant potency and selectivity for this receptor subtype. [32] Taking into account these experimental observations, we decided to synthesize new derivatives by replacing the furan moiety in position C2 of the PTP scaffold with the 1-(3-trifluoromethyl-benzyl)-1H-pyrazole-4-yl moiety present in the CVT 6975 (1) with the aim to better explore the role of this position in the receptor recognition and possibly obtain new A2B AR antagonists with non xanthinic structure (Fig 2)
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