Targeting P2X receptors for analgesia: Small molecule antagonists in development

Chronic and neuropathic pain management remains a considerable challenge in clinical practice, primarily due to the limited efficacy, adverse effects, and addictive potential of conventional analgesics, such as opioids and nonsteroidal anti-inflammatory drugs (NSAIDs). Recent studies highlight the significant role of purinergic signaling in pain processing, which positions P2X receptors (P2XRs) as promising targets for the development of non-opioid analgesics. This review summarizes the design and synthesis research progress of selective small molecule antagonists for P2X3R, P2X4R, and P2X7R from 2006 to 2026, focusing on structure-activity relationship (SAR) in vitro and analgesic effects in preclinical rodent pain models. For instance, Sivopixant is a highly selective P2X3R antagonist that exhibits potent analgesic efficacy in the rat spinal nerve ligation (SNL) model (ED₅₀ = 0.4 mg/kg p.o.) and possesses favorable pharmacokinetic properties. And NC-2600, as a potent and specific P2X4R antagonist, demonstrated significant analgesic efficacy in a rat model of colitis induced by 2,4-dinitrobenzene sulfonic acid (DNBS) at oral doses of 10 and 30 mg/kg. It has also completed Phase I clinical trials with a favorable safety profile. Additionally, A-740003 (49) is a potent, selective P2X7R antagonist that demonstrates broad-spectrum analgesic activity in both neuropathic and inflammatory pain models. These findings underline the potential of rational drug design to develop subtype-selective P2XR antagonists as novel analgesics for pain management.