Wang Yusui, Liu Shuyu, Zhang Zhikang, Ma Yunmeng, Qin Kexin, Du Jiahao, Wang Yu, Wang Bingxin, Qian Hai, Pang Xiaobin, Zhao Fenqin, Du Guanhua, Yan Lin
State Key Laboratory of Antiviral Drugs, School of Pharmacy, Henan University, N. Jinming Ave., Kaifeng, Henan, 475004, China.
State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing, Jiangsu, 210009, China.
Eur J Med Chem. 2025 Aug 5;292:117656. doi: 10.1016/j.ejmech.2025.117656. Epub 2025 Apr 18.
The pathophysiology of pain involves multiple signaling pathways, making its management a persistent clinical challenge. Transient receptor potential vanilloid 1 (TRPV1) acts as a molecular integrator of nociceptive stimuli in primary C-fiber sensory neurons and plays a crucial role in nociception, as well as in neuropathic and inflammatory pain. Numerous TRPV1 antagonists have been evaluated in clinical trials for various pathologies, including pain. However, their clinical development has been hindered by side effects such as hyperthermia and impaired noxious heat sensation. Additionally, these antagonists have limited efficacy when used as standalone therapies. Furthermore, studies have demonstrated a complex interplay between TRPV1 and μ-opioid receptor (MOR). In this study, dual-acting compounds targeting both TRPV1 and MOR were designed and synthesized using a pharmacophore fusion strategy, aimed at enhancing pain treatment, overcoming drug resistance, and minimizing the adverse effects typically associated with single-target drugs. Among these, compound 2ac demonstrated the highest in vitro potency, with an IC of 29.3 nM for TRPV1 antagonism and a K of 60.3 nM for MOR binding affinity. In vivo analgesic experiments conducted using a formalin-induced pain model in mice showed that compound 2ac exhibited a potent, dose-dependent anti-nociceptive effect. Target engagement studies confirmed that the analgesic effect of compound 2ac was attributed to both TRPV1 antagonism and MOR activation. Notably, further testing indicated that compound 2ac did not induce hyperthermia (a common side effect of TRPV1 antagonists) or lead to analgesic tolerance (a typical opioid-related adverse effect). Additionally, molecular docking studies showed strong compatibility of compound 2ac with the active sites of hMOR and hTRPV1, supporting its potential as a promising lead compound for pain management.
疼痛的病理生理学涉及多个信号通路，这使得疼痛管理成为一个持续存在的临床挑战。瞬时受体电位香草酸亚型1（TRPV1）在初级C纤维感觉神经元中作为伤害性刺激的分子整合器，在伤害感受以及神经性和炎性疼痛中起关键作用。许多TRPV1拮抗剂已在包括疼痛在内的各种疾病的临床试验中进行了评估。然而，它们的临床开发受到诸如体温过高和有害热感觉受损等副作用的阻碍。此外，这些拮抗剂作为单一疗法使用时疗效有限。此外，研究表明TRPV1与μ-阿片受体（MOR）之间存在复杂的相互作用。在本研究中，使用药效团融合策略设计并合成了靶向TRPV1和MOR的双作用化合物，旨在增强疼痛治疗效果、克服耐药性并将通常与单靶点药物相关的不良反应降至最低。其中，化合物2ac表现出最高的体外效力，对TRPV1拮抗作用的IC为29.3 nM，对MOR结合亲和力的K为60.3 nM。在小鼠福尔马林诱导的疼痛模型中进行的体内镇痛实验表明，化合物2ac表现出强效、剂量依赖性的抗伤害感受作用。靶点结合研究证实，化合物2ac的镇痛作用归因于TRPV1拮抗作用和MOR激活。值得注意的是，进一步测试表明化合物2ac不会诱导体温过高（TRPV1拮抗剂的常见副作用）或导致镇痛耐受性（典型的阿片类药物相关不良反应）。此外，分子对接研究表明化合物2ac与hMOR和hTRPV1的活性位点具有很强的兼容性，支持其作为疼痛管理有前景的先导化合物的潜力。
