TRPV4 agonist-1

TRPV4 agonist-1 is a transient receptor potential vanilloid 4 (TRPV4) agonist with an EC₅₀ value of 60nM in the hTRPV4 Ca²⁺ test^[1]. TRPV4 is a non-selective cation channel that can act as a cell sensor to sense mechanical stimulation, osmotic pressure changes, temperature and certain chemical signals, and plays an important role in the development of drugs for a variety of diseases^{[2, 3]}. TRPV4 agonist-1 can bind to the TRPV4 channel protein. The binding site is located in the cytoplasmic pocket formed between S1 and S4. TRPV4 agonist-1 binds to this pocket, causing the S4-S5 linker in the TRPV4 structure to move upward, thereby causing S6 to move, opening the TRPV4 channel and playing the role of an agonist^[4].

References:
[1] Atobe M, Nagami T, Muramatsu S, et al. Discovery of novel transient receptor potential vanilloid 4 (TRPV4) agonists as regulators of chondrogenic differentiation: Identification of quinazolin-4 (3 H)-ones and in vivo studies on a surgically induced rat model of osteoarthritis[J]. Journal of medicinal chemistry, 2019, 62(3): 1468-1483.
[2] Plant T D, Strotmann R. Trpv4[J]. Transient Receptor Potential (TRP) Channels, 2007: 189-205.
[3] Koskimäki S, Tojkander S. TRPV4—A multifunctional cellular sensor protein with therapeutic potential[J]. Sensors, 2024, 24(21): 6923.
[4] Zhen W, Zhao Z, Chang S, et al. Structural basis of ligand activation and inhibition in a mammalian TRPV4 ion channel[J]. Cell discovery, 2023, 9(1): 70.

TRPV4 agonist-1是一种瞬时受体电位香草素4（TRPV4）激动剂，在hTRPV4 Ca²⁺试验中的EC₅₀值为60nM^[1]。TRPV4是一种非选择性阳离子通道，能够作为细胞传感器参与感知机械刺激、渗透压变化、温度及某些化学信号，在针对多种疾病的药物开发中具有重要作用^{[2, 3]}。TRPV4 agonist-1能够与TRPV4通道蛋白结合，结合位点在S1至S4之间形成的朝向细胞质的口袋，TRPV4 agonist-1通过与该口袋结合，使TRPV4结构中的S4-S5 linker发生向上移动，进而引起S6移动，打开TRPV4通道，发挥激动剂的作用^[4]。