GTS 21 dihydrochloride is a selective partial agonist of the α7 nicotinic acetylcholine receptor (α7-nAChR), possessing anti-inflammatory and cognition-enhancing activities[1]. GTS 21 dihydrochloride also acts as an antagonist of the α4β2 nAChR (Ki=20nM) and the 5-HT3A receptor (IC50=3.1μM)[2]. GTS 21 dihydrochloride is utilized in research related to age-associated memory impairment (AAMI), Alzheimer's disease, schizophrenia, and acute lung injury[3-4].
In vitro, pretreatment of PC12 cells with GTS 21 dihydrochloride (3μM) for 10 minutes, followed by stimulation with ethanol (100mM) for 24 hours, significantly attenuated ethanol-induced cytotoxicity and suppressed the abnormal increase in intracellular calcium concentration[5]. In human renal tubular epithelial cells (HK-2), pretreatment with GTS 21 dihydrochloride (3–10μM) for 30 minutes prior to LPS (10μg/ml) stimulation for 24 hours significantly inhibited NF-κB nuclear translocation and the expression of the kidney injury marker NGAL, while also reducing the secretion of the chemokine CCL20, thereby mitigating macrophage migration and infiltration into renal tubular cells[6].
In vivo, in Leprdb/db mice aged 10-12 weeks, intraperitoneal administration of GTS 21 dihydrochloride (4mg/kg) twice a day for 8 weeks significantly improved renal function parameters, e.g. Blood Urea Nitrogen (BUN), creatinine, reduced levels of kidney injury markers (KIM-1, NGAL) and inflammatory cytokines (IL-6, HMGB-1), and alleviated glomerular mesangial matrix expansion and apoptosis[7]. In a septic acute kidney injury model induced by LPS (5mg/kg; i.p.) in C57BL/6J mice, a single pretreatment with GTS 21 dihydrochloride (20mg/kg; i.p.) 15 minutes prior to LPS challenge significantly lowered plasma TNF-α levels, BUN, and the expression of renal injury markers NGAL and KIM-1, while also reducing the number of apoptotic cells in kidney tissue[8].
References:
[1] Briggs CA, Anderson DJ, Brioni JD, et al. Functional characterization of the novel neuronal nicotinic acetylcholine receptor ligand GTS-21 in vitro and in vivo. Pharmacol Biochem Behav. 1997 May-Jun;57(1-2):231-41.
[2] Zhang R, White NA, Soti FS, et al. N-terminal domains in mouse and human 5-hydroxytryptamine3A receptors confer partial agonist and antagonist properties to benzylidene analogs of anabaseine. J Pharmacol Exp Ther. 2006 Jun;317(3):1276-84.
[3] Olincy A, Harris JG, Johnson LL, et al. Proof-of-concept trial of an alpha7 nicotinic agonist in schizophrenia. Arch Gen Psychiatry. 2006 Jun;63(6):630-8.
[4] Adams CE, Stevens KE, Kem WR, et al. Inhibition of nitric oxide synthase prevents alpha 7 nicotinic receptor-mediated restoration of inhibitory auditory gating in rat hippocampus. Brain Res. 2000 Sep 22;877(2):235-44.
[5] Li Y, King MA, Grimes J, et al. Alpha7 nicotinic receptor mediated protection against ethanol-induced cytotoxicity in PC12 cells. Brain Res. 1999 Jan 16;816(1):225-8.
[6] Yang A, Wu CH, Matsuo S, et al. Activation of the α7nAChR by GTS-21 mitigates septic tubular cell injury and modulates macrophage infiltration. Int Immunopharmacol. 2024 Sep 10;138:112555.
[7] Nakamura Y, Matsumoto H, Wu CH, et al. Alpha 7 nicotinic acetylcholine receptors signaling boosts cell-cell interactions in macrophages effecting anti-inflammatory and organ protection. Commun Biol. 2023 Jun 23;6(1):666.
[8] Meng Q, Tian X, Li J, et al. GTS-21, a selective alpha7 nicotinic acetylcholine receptor agonist, ameliorates diabetic nephropathy in Leprdb/db mice. Sci Rep. 2022 Dec 26;12(1):22360.
GTS 21 dihydrochloride是一种选择性α7烟碱乙酰胆碱受体（α7-nAChR）的部分激动剂，具有抗炎和增强认知的活性[1]。GTS 21 dihydrochloride也是α4β2 nAChR（Ki=20nM）和5-HT3A受体（IC50=3.1μM）的拮抗剂[2]。GTS 21 dihydrochloride可用于年龄相关记忆障碍、阿尔茨海默病、精神分裂症以及急性肺损伤等相关研究[3-4]。
在体外，GTS 21 dihydrochloride (3μM)预处理PC12细胞10分钟，随后以乙醇（100mM）刺激24小时，GTS 21 dihydrochloride显著减轻乙醇诱导的细胞毒性，并抑制细胞内钙离子浓度的异常升高[5]。GTS 21 dihydrochloride（3–10μM）预处理人肾小管上皮细胞（HK-2）30分钟，随后以LPS（10μg/ml）刺激24小时，GTS 21 dihydrochloride显著抑制NF-κB核转位及肾损伤标志物NGAL的表达，并降低趋化因子CCL20的分泌，从而减轻巨噬细胞向肾小管细胞的迁移浸润[6]。
在体内，GTS 21 dihydrochloride（4mg/kg）每日两次腹腔注射，持续8周，用于处理10-12周龄的Leprdb/db小鼠，显著改善肾功能指标包括血尿素氮（BUN）、肌酐，降低肾损伤标志物（KIM-1、NGAL）及炎症因子（IL-6、HMGB-1）水平，并减轻肾小球系膜基质扩张和细胞凋亡[7]。GTS 21 dihydrochloride（20mg/kg）单次腹腔注射15分钟前处理C57BL/6J，随后给予LPS（5mg/kg）腹腔注射诱导脓毒症急性肾损伤模型。GTS 21 dihydrochloride显著降低野生型小鼠血浆TNF-α水平、BUN及肾脏损伤标志物NGAL、KIM-1表达，并减少肾组织凋亡细胞数量[8]。