Discovery of Potent Antiallodynic Agents for Neuropathic Pain Targeting P2X3 Receptors.
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 ED50values 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.
School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Young-Hwan
YH
Jung
Yeo Ok
YO
Kim
Hai
H
Lin
New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF) , 80 Cheombok-ro, Dong-gu, Daegu 41061, Republic of Korea.
Joong-Heui
JH
Cho
New Drug Development Center (NDDC), Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF) , 80 Cheombok-ro, Dong-gu, Daegu 41061, Republic of Korea.
Jin-Hee
JH
Park
School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
So-Deok
SD
Lee
Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Jinsu
J
Bae
School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Koon Mook
KM
Kang
College of Pharmacy, Dankook University , Cheonan 330-714, Republic of Korea.
Yoon-Gyoon
YG
Kim
Convergence Research Center for Diagnosis, Treatment and Care System of Dementia, Korea Institute of Science and Technology , PO Box 131, Cheongryang, Seoul 130-650, Republic of Korea.
Ae Nim
AN
Pae
School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Hyojin
H
Ko
School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Chul-Seung
CS
Park
Myung Ha
MH
Yoon
School of Life Sciences, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.|Department of Biomedical Science and Engineering, Gwangju Institute of Science and Technology (GIST) , Gwangju 500-712, Republic of Korea.
Yong-Chul
0000-0003-1520-2011
YC
Kim
D018712:Analgesics, Non-Narcotic / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D057809:HEK293 Cells; D006801:Humans; D008026:Ligation; D008297:Male; D051379:Mice; D015394:Molecular Structure; D009437:Neuralgia / Q000188:drug therapy* / Q000378:metabolism; D009865:Oocytes; D018408:Patch-Clamp Techniques; D010539:Permeability; D058920:Purinergic P2X Receptor Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D058477:Receptors, Purinergic P2X3 / Q000378:metabolism; D013127:Spinal Nerves; D013329:Structure-Activity Relationship; D014981:Xenopus
D018712:Analgesics, Non-Narcotic; D000970:Antineoplastic Agents; D058920:Purinergic P2X Receptor Antagonists; D011725:Pyridines; D058477:Receptors, Purinergic P2X3
Neuropathic pain; P2X3 receptor; adenosine 5′-triphosphate; antagonist; antiallodynic effect; structure−activity relationship