In pursuit of P2X3 antagonists: novel therapeutics for chronic pain and afferent sensitization

Abstract

Treating pain by inhibiting ATP activation of P2X3-containing receptors heralds an exciting new approach to pain management, and Afferent's program marks the vanguard in a new class of drugs poised to explore this approach to meet the significant unmet needs in pain management. P2X3 receptor subunits are expressed predominately and selectively in so-called C- and Aδ-fiber primary afferent neurons in most tissues and organ systems, including skin, joints, and hollow organs, suggesting a high degree of specificity to the pain sensing system in the human body. P2X3 antagonists block the activation of these fibers by ATP and stand to offer an alternative approach to the management of pain and discomfort. In addition, P2X3 is expressed pre-synaptically at central terminals of C-fiber afferent neurons, where ATP further sensitizes transmission of painful signals. As a result of the selectivity of the expression of P2X3, there is a lower likelihood of adverse effects in the brain, gastrointestinal, or cardiovascular tissues, effects which remain limiting factors for many existing pain therapeutics. In the periphery, ATP (the factor that triggers P2X3 receptor activation) can be released from various cells as a result of tissue inflammation, injury or stress, as well as visceral organ distension, and stimulate these local nociceptors. The P2X3 receptor rationale has aroused a formidable level of investigation producing many reports that clarify the potential role of ATP as a pain mediator, in chronic sensitized states in particular, and has piqued the interest of pharmaceutical companies. P2X receptor-mediated afferent activation has been implicated in inflammatory, visceral, and neuropathic pain states, as well as in airways hyperreactivity, migraine, itch, and cancer pain. It is well appreciated that oftentimes new mechanisms translate poorly from models into clinical efficacy and effectiveness; however, the breadth of activity seen from P2X3 inhibition in models offers a realistic chance that this novel mechanism to inhibit afferent nerve sensitization may find its place in the sun and bring some merciful relief to the torment of persistent discomfort and pain. The development philosophy at Afferent is to conduct proof of concept patient studies and best identify target patient groups that may benefit from this new intervention.

Urothelial Signaling

“…In addition, augmented release of transmitters, most notably ATP, from the urothelium can lead to painful sensations by excitation of purinergic receptors on sensory fibers both peripherally and centrally (43,56,267). Thus inhibition of purinergic P2X3 receptors has been shown to be effective in suppressing afferent excitation in various animal models and may be effective in clinical conditions associated with pain such as BPS/IC (101,113). Onabotulinum toxin A (BoNT-A) has been used in the treatment of lower urinary tract disorders including BPS/IC and appears to have a positive therapeutic effect (64).…”

“…In several animal models, selective dual P2X3, P2X2/3 antagonists have been shown to be effective at reducing nocifensive responses, hyperalgesia, and allodynia (150,151). New drugs are in development (101,102,113), but so far no clinical experiences have been published.…”

P2Y purinergic receptors: New targets for analgesic and antimigraine drugs

“…With the recent discovery of innovative chemical scaffolds for P2X3 antagonists, the first Phase 2 "proof-of-concept" studies are currently underway for inflammatory, visceral, and neuropathic pain patients [28].…”

“…), but by the use of various in vivo models for the pre-clinical study of these types of pain. It has proven to be extremely difficult to draw generalized conclusions based on in vitro or pre-clinical in vivo data, apart from one specific type of pain (visceral pain) where the P2X3 subtype plays a prominent role [28]. Moreover, the large number of P2 receptor subtypes involved (to which P1 receptors responding to adenosine should be added also) [3], and long-standing lack of selective ligands to clearly identify the roles of specific P2 receptor subtypes in preclinical studies has complicated the identification of specific purinergic targets.…”

Differential Expression and Pharmacology of Native P2X Receptors in Rat and Primate Sensory Neurons

“…TNP-ATP [2-O-(2,4,6-trinitrophenyl)-ATP] (Jarvis et al, 2001), A-317491 (McGaraughty et al, 2003), and RO51 ) are P2X3/P2X2/3 antagonists that have shown reduced hyperalgesia and mechanical allodynia in inflammatory and neuropathic pain models. P2X3/P2X2/3 antagonists are currently being tested in the clinic, so their analgesic efficacy has yet to be established in patients (Ford, 2012). Progress in the discovery of novel analgesics has been hampered by limited predictability of efficacy from preclinical animal studies to validation in humans (Mogil et al, 2010).…”