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The 1,2,4-triazolo[1,5- a ]quinoxaline (TQX) scaffold was extensively investigated in our previously reported studies and recently, our attention was focused at position 5 of the tricyclic nucleus where different acyl and carboxylate moieties were introduced (compounds 2 – 15 ). This study produced some interesting compounds endowed with good hA 3 receptor affinity and selectivity. In addition, to find new insights about the structural requirements for hA 3 receptor–ligand interaction, the tricyclic TQX ring was destroyed yielding some 1,2,4-triazole derivatives (compounds 16 – 23 ). These simplified compounds, though maintaining the crucial structural requirements for adenosine receptor–ligand interaction, have a very low hA 3 adenosine receptor affinity, the only exception being compound 23 (1-[3-(4-methoxyphenyl)-1-phenyl-1 H -1,2,4-triazol-5-yl]-3-phenylurea) endowed with a K i value in the micro-molar range and high hA 3 selectivity versus both hA 1 and hA 2A AR subtypes. Evaluation of the side products obtained in the herein reported synthetic pathways led to the identification of some new triazolo[1,5- a ]quinoxalines as hA 3 AR antagonists (compounds 24 – 27 ). These derivatives, though lacking the classical structural requirements for the anchoring at the hA 3 receptor site, show high hA 3 affinity and in some case selectivity versus hA 1 and hA 2A subtypes. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA 3 receptor. [ABSTRACT FROM AUTHOR]

Abstract: A number of 5-oxo-pyrazolo[1,5-c]quinazolines (series B-1), bearing at position-2 the claimed (hetero)aryl moiety (compounds 1–8) but also a carboxylate group (9–14), were designed as hA3 AR antagonists. This study produced some interesting compounds endowed with good hA3 receptor affinity and high selectivity, being totally inactive at all the other AR subtypes. In contrast, the corresponding 5-ammino derivatives (series B-2) do not bind or bind with very low affinity at the hA3 AR, the only exception being the 5-N-benzoyl compound 19 that shows a hA3 K i value in the high μ-molar range. Evaluation of the synthetic intermediates led to the identification of some 5(3)-(2-aminophenyl)-3(5)-(hetero)arylpyrazoles 20–24 with modest affinity but high selectivity toward the hA3 AR subtype. Molecular docking of the herein reported tricyclic and simplified derivatives was carried out to depict their hypothetical binding mode to our model of hA3 receptor. [Copyright &y& Elsevier]

Abstract: This paper reports the study of new 2-phenyl- and 2-methylpyrazolo[3,4-c]quinolin-4-ones (series A) and 4-amines (series B), designed as adenosine receptor (AR) antagonists. The synthesized compounds bear at the 6-position various groups, with different lipophilicity and steric hindrance, that were thought to increase human A1 and A2A AR affinities and selectivities, with respect to those of the parent 6-unsubstituted compounds. In series A, this modification was not tolerated since it reduced AR affinity, while in series B it shifted the binding towards the hA1 subtype. To rationalize the observed structure–affinity relationships, molecular docking studies at A2AAR-based homology models of the A1 and A3 ARs and at the A2AAR crystal structure were carried out. [Copyright &y& Elsevier]

Abstract: The study of novel 2-arylpyrazolo[3,4-c]quinolin-4-(hetero)arylamides, designed as human (h) A3 adenosine receptor antagonists, is reported. The new derivatives are endowed with nanomolar hA3 receptor affinity and high selectivity versus hA1, hA2A and hA2B receptors. Among the (hetero)aroyl residues introduced on the 4-amino group, the 2-furyl and 4-pyridyl rings turned out to be the most beneficial for hA3 affinity (K i =3.4 and 5.0nM, respectively). An intensive molecular docking study to a rhodopsin-based homology model of the hA3 receptor was carried out to obtain a ‘structure-based pharmacophore model’ that proved to be helpful for the interpretation of the observed affinities of the new hA3 pyrazoloquinoline antagonists. [Copyright &y& Elsevier]

Abstract: The study of some 4-substituted-2-aryl-1,2,4-triazolo[4,3-a]quinoxalin-1-one derivatives, designed as hA3 adenosine receptor antagonists, is reported. The new compounds bear on the four-position different acylamino, sulfonylamino, benzylureido and benzyloxy moieties, which have also been combined with a para-methoxy group on the 2-phenyl ring or with a nitro residue at the six-position. Many derivatives show high hA3 adenosine receptor affinities and selectivities both versus hA1 and hA2A receptors. The observed structure–affinity relationships of this class of antagonists have been exhaustively rationalized using the recently published ligand-based homology modeling (LBHM) approach. The selected 4-bismethanesulfonylamino-2-phenyl-1,2,4-triazolo[4,3-a]quinoxalin-1-one (13), which shows high hA3 affinity (K i =5.5nM) and selectivity versus hA1, hA2A (both selectivity ratios>1800) and hA2B (cAMP assay, IC50 >10,000nM) receptors, was tested in an in vitro rat model of cerebral ischemia, proving to be effective in preventing the failure of synaptic activity, induced by oxygen and glucose deprivation in the hippocampus, and in delaying the occurrence of anoxic depolarization. [Copyright &y& Elsevier]

Abstract: Some 2-aryl-8-chloro-1,2,4-triazolo[1,5-a]quinoxaline derivatives 2–18, obtained by introducing different substituents on either the 4-amino moiety (acyl or carbamoyl groups) or the 2-phenyl ring (4-OCH3) of previously reported 8-chloro-2-phenyl-1,2,4-triazolo[1,5-a]quinoxalin-4-amine (1), have been synthesized and tested in radioligand binding assays at bovine A1 and A2A and at cloned human A1 and A3 adenosine receptors. The rationally designed 8-chloro-2-(4-methoxy-phenyl)-1,2,4-triazolo[1,5-a]quinoxalin-4-acetylamine (14) can be considered one of the most potent and hA3 versus hA1 selective AR antagonists reported till now. The structure–activity relationships of compounds 2–18 are in agreement with those of previously reported 2-aryl-1,2,4-triazolo[4,3-a]quinoxalines (series A) and 2-arylpyrazolo[3,4-c]quinolines (series B), thus suggesting a similar AR binding mode. In fact, the importance for the A3 receptor–ligand interaction of both a strong acidic NH proton donor and a Cacceptor at position-4, able to engage hydrogen-bonding interactions with specific sites on the A3 AR, has been confirmed. Using our recently published hA3 receptor model, to better elucidate our experimental results, we decided to theoretically depict the putative TM binding motif of the herein reported 1,2,4-triazolo[1,5-a]quinoxaline derivatives on human A3 receptor. Structure–activity relationships have been explained analyzing the three-dimensional structure of the antagonist-receptor models obtained by molecular docking simulation. [Copyright &y& Elsevier]

Since most of the reported adenosine receptor antagonists are 2-(hetero)aryl-substituted tricyclic heteroaromatic derivatives, in the present study we report the synthesis and the biological evaluation of a new set of 4-amino-1,2,4-triazolo[1,5-a]quinoxalines containing at position-2 an ethyl carboxylate group or a hydrogen atom. The structure–activity relationships on these compounds were in accordance with those of a previously reported series of analogous size and shape, thus suggesting a similar A1-binding mode. In particular, the binding data indicate that alkylation of the 4-amino group of these derivatives lead to potent A1-receptor antagonists. Moreover, as new results, this study has pointed out that the ethyl 2-carboxylate group can advantageously replace the 2-(hetero)aryl ring of previously reported triazoloquinoxaline derivatives, affording an ameliorated interaction with the A1-receptor subtype. [Copyright &y& Elsevier]