Thus far, few antagonists of P2X3 and P2X2/3 have been identified. One of them, A-317491, has shown to reduce mechanical allodynia and thermal hyperalgesia following chronic nerve constriction.149,150 AF-353 is another P2X3 receptor antagonist that has shown similar potency for human and rat recombinant P2X3 homotrimers (IC50 = 8.7 and IC50 = 8.9 nM, respectively).151 A prodrug version of AF-353, (RO-51), has been developed to treat urological dysfunction and chronic pain.152 A recently marketed P2X3R antagonist, gefapixant (AF-219, MK-7264), is used for reduction of exaggerated, persistent, and frequent urge to cough as a result of hypersensitized sensory neurons, triggered by injury or infection.153-155 Recently, a series of 5-hydroxy pyridine derivatives were synthesized and evaluated for their activities at hP2X3 receptors.156 One of the compounds in this series, prodrug 28, has shown antiallodynic activity in spinal nerve ligation and chemotherapy-induced peripheral neuropathy in rats.156 This and other data on the P2X3R antagonists indicate that targeting the P2X3 receptors could be a promising treatment for neuropathic pain. Thus far, there is no identified PET radioligand for evaluation of the P2X3 receptors, to the best of our knowledge.
