Jung, Young-Hwan Kim, Yeo Ok Lin, Hai Cho, Joong-Heui Park, Jin-Hee Lee, So-Deok Bae, Jinsu Kang, Koon Mook Kim, Moon-Gyoon Pae, Ae Nim Ko, Hyojin Park, Chul-Seung Yoon, Myung Ha Kim, Yong-Chul 2024-01-20T01:03:43Z 2024-01-20T01:03:43Z 2021-09-05 2017-07 1948-7193 https://pubs.kist.re.kr/handle/201004/122583 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 A delta-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. English AMER CHEMICAL SOC DIELS-ALDER REACTIONS SENSORY NEURONS PYRIDINE-DERIVATIVES RAT MODEL P2X(3) ANTAGONIST ATP SENSITIZATION ANALGESICS ALLODYNIA Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors Article 10.1021/acschemneuro.6b00401 1 ACS CHEMICAL NEUROSCIENCE, v.8, no.7, pp.1465 - 1478 ACS CHEMICAL NEUROSCIENCE 8 7 1465 1478 scie scopus 000406174500008 2-s2.0-85024883644 Biochemistry & Molecular Biology Chemistry, Medicinal Neurosciences Biochemistry & Molecular Biology Pharmacology & Pharmacy Neurosciences & Neurology Article DIELS-ALDER REACTIONS SENSORY NEURONS PYRIDINE-DERIVATIVES RAT MODEL P2X(3) ANTAGONIST ATP SENSITIZATION ANALGESICS ALLODYNIA Neuropathic pain antiallodynic effect P2X3 receptor adenosine 5 &apos -triphosphate antagonist structure-activity relationship