新規Nr4a1拮抗薬は神経障害性および骨がん痛モデルマウスのアロディニア反応を抑制する

• Published in: 日本薬理学会年会要旨集 p. 2-P-131
• Main Authors: 合田, 浩明, 宮田, 篤郎, 伊東, 樹穂, 岡田, 卓哉, 黒田, 翼, 髙﨑, 一朗, 磯, 芹奈, 豊岡, 尚樹, 栗原, 崇
• Format: Journal Article
• Language: Japanese
• Published: 公益社団法人 日本薬理学会 2022
• Subjects: antagonist; nociception; pain
• ISSN: 2435-4953
• DOI: 10.1254/jpssuppl.95.0_2-P-131

Previously, we found that intrathecal (i.t.) injection of PACAP induces long-lasting mechanical allodynia in mice and increases the expression of Nr4a1 (Nuclear receptor subfamily 4, group A, member 1) mRNA in the spinal cord. We also developed a novel small-molecule antagonist of Nr4a1, named NRA-8, using docking-based in silico screening followed by in vitro/vivo pharmacological assays. NRA-8 (i.t.) showed to be able to inhibit the induction of PACAP-induced long-lasting mechanical allodynia. In this study, based on the structure of NRA-8, we synthesized derivative compounds with potent antagonistic activity on Nr4a1 and examined their analgesic effects on pain model mice.We synthesized 15 novel derivative compounds of NRA-8 (NRA-801 to 815) and identified that 4 derivatives (NRA-811, NRA-813 to 815) show more potent antagonist activity than NRA-8. Among 4 derivatives, the effects of NRA-811 and 815 on mechanical allodynia were investigated. I.t. injection of Nr4a1 antagonists (1 nmol) ameliorated the spinal nerve ligation-induced mechanical allodynia. In bone cancer pain model mice which are induced by transplantation of NCTC2472 cells into the femur, oral administration of Nr4a1 antagonists (10 and 30 mg/kg) dose-dependently ameliorated the mechanical allodynia. In both cases, NRA-815 showed the strongest effects than NRA-811 or NRA-8. Inhibiting Nr4a1 may be one of the strategies in the treatment of intractable pain.