Do Nayeon, Zuo Dongxu, Kim Miri, Kim Minseok, Ha Hee-Jin, Blumberg Peter M, Ann Jihyae, Hwang Sun Wook, Lee Jeewoo
College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
Department of Biomedical Sciences, Korea University College of Medicine, Seoul 02841, Republic of Korea.
Pharmaceuticals (Basel). 2024 Sep 13;17(9):1209. doi: 10.3390/ph17091209.
Pain management remains a major challenge in medicine, highlighting the need for the development of new therapeutic agents. The transient receptor potential ankyrin 1 (TRPA1) and vanilloid 1 (TRPV1) are ion channels that play key roles in pain perception. Targeting both TRPA1 and TRPV1 simultaneously with dual antagonists offers a promising approach to pain relief. In this study, we investigated a series of hybrid analogs of TRPA1 and TRPV1 antagonists to discover novel therapeutic agents for pain. Among these compounds synthesized by a condensation reaction forming 1,2,4-oxadiazole between the A- and C-regions, compound exhibited substantial dual-acting antagonism to TRPA1 and TRPV1 with IC values of 1.42, 2.84, 2.13, and 5.02 μM for hTRPA1, mTRPA1, hTRPV1, and rTRPV1, respectively. In the formalin test, compound demonstrated dose-dependent analgesic activity with an ED of 85.9 mg/kg in phase 1 and 21.6 mg/kg in phase 2, respectively, and was able to inhibit pain behavior completely at a dose of 100 mg/kg. This study presents the discovery and characterization of a novel dual TRPA1/TRPV1 antagonist, highlighting its potential as a therapeutic agent for pain management.
疼痛管理仍然是医学上的一项重大挑战，这凸显了开发新型治疗药物的必要性。瞬时受体电位锚蛋白1（TRPA1）和香草酸受体1（TRPV1）是在疼痛感知中起关键作用的离子通道。同时用双重拮抗剂靶向TRPA1和TRPV1为缓解疼痛提供了一种有前景的方法。在本研究中，我们研究了一系列TRPA1和TRPV1拮抗剂的杂合类似物，以发现用于疼痛治疗的新型治疗药物。在通过A区和C区之间形成1,2,4-恶二唑的缩合反应合成的这些化合物中，化合物对hTRPA1、mTRPA1、hTRPV1和rTRPV1表现出显著的双重作用拮抗作用，IC值分别为1.42、2.84、2.13和5.02μM。在福尔马林试验中，化合物表现出剂量依赖性镇痛活性，在第1阶段的ED为85.9mg/kg，在第2阶段为21.6mg/kg，并且在100mg/kg的剂量下能够完全抑制疼痛行为。本研究介绍了一种新型双重TRPA1/TRPV1拮抗剂的发现和特性，突出了其作为疼痛管理治疗药物的潜力。
