The P2X7 receptor (P2X7R) is a nonselective cation channel that is activated by extracellular ATP and triggers the secretion of several proinflammatory substances, such as IL-1β, IL-18, TNF-α, and nitric oxide. Recently, several preclinical studies have demonstrated that this receptor participates in inflammation and pain mechanisms. Taken together, these results indicate that P2X7R is a promising pharmacological target, and compounds that modulate the function of this receptor show potential as new anti-inflammatory medicines. In this review, we discuss aspects of P2X7R pharmacology and the participation of this protein in inflammation and pain and provide an overview of some promising compounds that have been tested as antagonists of P2X7R, with clinical applicability.

Natural products contribute significantly to available drug therapies and have been a rich source for scientific investigation. In general, due to their low cost and traditional use in some cultures, they are an object of growing interest as alternatives to synthetic drugs. With several diseases such as cancer, and inflammatory and neuropathic diseases having been linked to the participation of purinergic (P2) receptors, there has been a flurry of investigations on ligands within natural products. Thirty-four different sources of these compounds have been found so far, that have shown either agonistic or antagonistic effects on P2 receptors. Of those, nine different plant sources demonstrated effects on P2X2, P2X3, P2X7, and possibly P2Y12 receptor subtypes. Microorganisms, which represent the largest group, with 26 different sources, showed effects on both receptor subtypes, ranging from P2X1 to P2X4 and P2X7, and P2Y1, P2Y2, P2Y4, and P2Y6. In addition, there were seventeen animal sources that affected P2X7 and P2Y1 and P2Y12 receptors. Natural products have provided some fascinating new mechanisms and sources to better understand the P2 receptor antagonism. Moreover, current investigations should clarify further pharmacological mechanisms in order to consider these products as potential new medicines.

Nucleotides and nucleosides act as potent extracellular messengers via the activation of the family of cell-surface receptors termed purinergic receptors. These receptors are categorized into P1 and P2 receptors (P2Rs). P2Rs are further classified into two distinct families, P2X receptors (P2XRs) and P2Y receptors (P2YRs). These receptors display broad tissue distribution throughout the body and are involved in several biological events. Immune cells express various P2Rs, and purinergic signaling mechanisms have been shown to play key roles in the regulation of many aspects of immune responses. Researchers have elucidated the involvement of these receptors in the host response to infections. The evidences indicate a dual function of these receptors, depending on the microorganism and the cellular model involved. Three recent reports have examined the relationship between the level of extracellular ATP, the mechanisms underlying purinergic receptors participating in the infection mechanism of HIV-1 in the cell. Although preliminary, these results indicate that purinergic receptors are putative pharmacological targets that should be further explored in future studies.