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 ED50 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.

• Authors: Young-Hwan Jung, Yeo Ok Kim, Hai Lin, Joong-Heui Cho, Jin-Hee Park, So-Deok Lee, Jinsu Bae, Koon Mook Kang, Yoon-Gyoon Kim, Ae Nim Pae, Hyojin Ko, Chul-Seung Park, Myung Ha Yoon, Yong-Chul Kim
• Journal: ACS chemical neuroscience (ACS Chem Neurosci) Vol. 8 Issue 7 Pg. 1465-1478 (07 19 2017) ISSN: 1948-7193 [Electronic] United States
• PMID: 28323403 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Analgesics, Non-Narcotic
• Antineoplastic Agents
• Purinergic P2X Receptor Antagonists
• Pyridines
• Receptors, Purinergic P2X3

Topics

• Analgesics, Non-Narcotic (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Animals
• Antineoplastic Agents
• Brain (drug effects, metabolism)
• Disease Models, Animal
• HEK293 Cells
• Humans
• Ligation
• Male
• Mice
• Molecular Structure
• Neuralgia (drug therapy, metabolism)
• Oocytes
• Patch-Clamp Techniques
• Permeability
• Purinergic P2X Receptor Antagonists (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Pyridines (chemical synthesis, chemistry, pharmacokinetics, pharmacology)
• Rats
• Receptors, Purinergic P2X3 (metabolism)
• Spinal Nerves
• Structure-Activity Relationship
• Xenopus