Objective-Foam cell (FC) formation by oxidized low-density lipoprotein (oxLDL) accumulation in macrophages is crucial for development of atherosclerosis. Hypoxia has been demonstrated in atherosclerosis and hypoxia-inducible factor-1 (HIF-1) has been shown to promote intraplaque angiogenesis and FC development. M acrophage foam cell formation is an important process in atherosclerotic plaque development. 1 Atherosclerosis is initiated by dysfunction of endothelial cells at lesionprone sites in the walls of arteries, which results in monocyte infiltration into the arterial intima. These cells differentiated into macrophages, which then internalize large amounts of oxidized low-density lipoprotein forming cholesterol-laden macrophages called "foam cells" (FCs), which in turn give rise to fatty streaks in the arterial wall. 2 As the atherosclerotic lesion develops, the arterial wall thickness increases and oxygen diffusion into the intima is markedly reduced. These hypoxic regions contain large number of FCs revealing that these cells experience hypoxia during the development of atherosclerotic lesions. 3-4 Hypoxia-inducible factor-1 (HIF-1), the most important factor involved in the cellular response to hypoxia, is a heterodimeric transcription factor composed of an inducibly expressed HIF-1␣ subunit and a constitutively-expressed HIF-1␤ subunit. 5 It is well established that HIF plays a major role in vascular endothelial growth factor (VEGF) expression and angiogenesis, mediating important alterations associated with atherogenesis and angiogenic activity of macrophages. 6 -7 Moreover, under atherogenic conditions, the high expression of HIF-1 in macrophages promotes FC formation and atherosclerosis. 8

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Adenosine is a potent extracellular messenger that is produced in high concentrations under metabolically unfavourable conditions. Tissue hypoxia, consequent to a compromised cellular energy status, is followed by the enhanced breakdown of ATP leading to the release of adenosine. Through the interaction with A2 and A3 membrane receptors, adenosine is devoted to the restoration of tissue homeostasis, acting as a retaliatory metabolite. Several aspects of the immune response have to be taken into consideration and even though in general it is very important to dampen inflammation, in some circumstances, such as the case of cancer, it is also necessary to increase the activity of immune cells against pathogens. Therefore, adenosine receptors that are defined as ‘sensors–of metabolic changes in the local tissue environment may be very important targets for modulation of immune responses and drugs devoted to regulating the adenosinergic system are promising in different clinical situations.

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The characterization of the native and recombinant P2X7 receptor continues to be hindered by the lack of specific and subtype-selective antagonists with a "druglike" profile. However, a tyrosine derivative named KN-62 exhibits selective P2X7 receptor-blocking properties. As a molecular simplification of KN-62, the present study was designed to evaluate the functional antagonistic properties of a novel series of glycine derivatives characterized by the presence of different phenyl-substituted piperazine moieties. Antagonistic activity of these glycine derivatives was tested on HEK293 cells transfected with the human P2X7 receptor. The most potent P2X7 receptor antagonist identified in this study (compound 4g) contains an o-fluorine substituent on the phenylpiperazine moiety and had an IC50 of 12.1 nM. The biological responses investigated were ATP-dependent Ca2+ influx across the plasma membrane and ethidium bromide uptake.