UNC9995

UNC9995 is a β-arrestin2-biased agonist of dopamine receptor Drd2. UNC9995 inhibits NLRP3 inflammasome activation by enhancing β-arrestin2-NLRP3 interaction, thus prevents neuronal degeneration. Futhermore, UNC9995 activates the Drd2/β-arrestin2 signaling to prevent inflammation-related genes transcription-induced by JAK/STAT3. UNC9995 improves depressive behavior in mouse model, and improves astrocytes dysfunctions[1].

Signaling Pathways >> GPCR/G Protein >> Dopamine Receptor

Research Areas >> Inflammation/Immunology

Signaling Pathways >> Neuronal Signaling >> Dopamine Receptor

D2 Receptor

UNC9995（10 μM；1 小时）预处理原代星形胶质细胞，使它受IL-6（300 ng/mL；24 小时）诱导后，STAT3 和 β-arrestin2 的结合得到增强。它还抑制 STING、TBK1、JAK 的激活[1]。 UNC9995（1、5、10 和 20 μM；1 小时）能够消除细胞凋亡和炎症，当用 IL-6 (300 ng/mL；24 小时) 刺激 WT 和 Arrb2−/− 星形胶质细胞后[1]。 Western Blot Analysis[1] Cell Line: Primary astrocytes Concentration: 10 μM Incubation Time: 1 h for pre-incubation; with 300 ng/mL IL-6 Result: Enhanced the interaction between STAT3 and β-arrestin2. Abolished the activation of cGAS-STING and JAK/STAT3 pathway stimulated by IL-6, decreased the level of p-STING, p-TBK1, p-JAK.

UNC9995（2 mg/kg/天，腹腔注射，2 周）在小鼠的慢性社交失败应激 (CSDS) 模型和慢性不可预知轻度应激 (CUMS) 模型中，改善了抑郁样行为表型并改善海马体中星形胶质细胞的丢失[1]。 Animal Model: Chronic unpredictable mild stress (CUMS) mouse model[1] Dosage: 2 mg/kg/d Administration: IP; 2 weeks Result: Improved depressive-like symptoms of CUMS mouse model in WT mice but not Arrb2−/− mice.

[1]. Liu Y, et al. β-Arrestin2-biased Drd2 agonist UNC9995 alleviates astrocyte inflammatory injury via interaction between β-arrestin2 and STAT3 in mouse model of depression. J Neuroinflammation. 2022 Oct 1;19(1):240.