Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors

Abstract

Antagonism of the P2X3 receptor is one of the potential therapeutic strategies for the management of neuropathic pain because P2X3 receptors are predominantly localized on small to medium diameter C- and Aδ-fiber primary afferent neurons, which are related to the pain-sensing system. In this study, 5-hydroxy pyridine derivatives were designed, synthesized, and evaluated for their in vitro biological activities by two-electrode voltage clamp assay at hP2X3 receptors. Among the novel hP2X3 receptor antagonists, intrathecal treatment of compound 29 showed parallel efficacy with pregabalin (calcium channel modulator) and higher efficacy than AF353 (P2X3 receptor antagonist) in the evaluation of its antiallodynic effects in spinal nerve ligation rats. However, because compound 29 was inactive by intraperitoneal administration in neuropathic pain animal models due to low cell permeability, the corresponding methyl ester analogue, 28, which could be converted to compound 29 in vivo, was investigated as a prodrug concept. Intravenous injection of compound 28 resulted in potent antiallodynic effects, with ED values of 2.62 and 2.93 mg/kg in spinal nerve ligation and chemotherapy-induced peripheral neuropathy rats, respectively, indicating that new drug development targeting the P2X3 receptor could be promising for neuropathic pain, a disease with high unmet medical needs.

Modulation of Pathological Pain by Epidermal Growth Factor Receptor

“…To that end, a variety of emerging potential therapeutic agents for neuropathic pain are being repositioned or developed for clinical trial. These include monoclonal antibodies against inflammatory mediators, cannabinoids, and inhibitors of G protein-coupled receptors and N-methyl- D -aspartate receptors ( Figure 1B ) ( Karppinen et al, 2003 ; Stahel et al, 2016 ; Jung et al, 2017 ; Wang et al, 2017 ; Aiyer et al, 2018 ; Mapplebeck et al, 2018 ; Kreutzwiser and Tawfic, 2019 ; Alkislar et al, 2020 ; Haleem and Wright, 2020 ; Kushnarev et al, 2020 ; Maayah et al, 2020 ; Yu et al, 2020 ; Zhang W. et al, 2020 ; Matarazzo et al, 2021 ).…”

Purinergic Receptors of the Central Nervous System: Biology, PET Ligands, and Their Applications

“…[153][154][155] Recently, a series of 5-hydroxy pyridine derivatives were synthesized and evaluated for their activities at hP2X 3 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 P2X 3 R antagonists indicate that targeting the P2X 3 receptors could be a promising treatment for neuropathic pain.…”

“…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 P2X 3 R antagonists indicate that targeting the P2X 3 receptors could be a promising treatment for neuropathic pain. Thus far, there is no identified PET radioligand for evaluation of the P2X 3 receptors, to the best of our knowledge.…”

Basic/Translational Development of Forthcoming Opioid- and Nonopioid-Targeted Pain Therapeutics

“…P2X3 antagonists have shown efficacy in inflammatory and in mono and poly neuropathic pain states. 242 P2X4 subtype is important in spinal facilitation that originated from tissue and nerve injury. 243 P2X4R antisense oligodeoxynucleotide intrathecal delivery prevented P2X4R protein expression and restrained mechanical allodynia development.…”