Luzindole

Luzindole is a selective melatonin receptor (MT) antagonist, with a Ki value of 158nM for MT1 and 10.2nM for MT2^[1]. Luzindole preferentially acts on the MT2 (Mel1b) receptor^[2]. Luzindole can be used to evaluate the role of melatonin receptor signaling in various pathways, including circadian rhythms, animal behavior, and melanocyte responses, both in vitro and in vivo^[3]. Luzindole can also inhibit experimental autoimmune encephalomyelitis (EAE) and has antidepressant effects^[4].

In vitro, Luzindole (200μM) pre-treatment of Cal27 tongue squamous cell carcinoma cells for 2 hours, followed by co-incubation with 2mM melatonin for 24 hours, blocked the promotion of melatonin on TFE3 (transcription factor E3) dephosphorylation and nuclear translocation, thereby inhibiting the autophagy process and increasing Caspase-3 activity^[5]. Luzindole (10nM, 100nM, and 100mM) pre-treatment of estrogen receptor-positive Ishikawa endometrial cancer cells for 96 hours, followed by co-incubation with 1nM melatonin, completely blocked the inhibitory effect of melatonin on cell proliferation^[6].

In vivo, Luzindole (0.35mg/kg) alone or in combination with lipopolysaccharide (LPS, 1.25mg/kg), administered by intraperitoneal injection to Swiss mice for 1.5 hours, can induce intestinal inflammation and morphological changes. Luzindole treatment alone led to shortened villus height, reduced goblet cell count, increased levels of non-protein sulfhydryls (NP-SHs), and decreased catalase (CAT) activity^[7]. Luzindole (40mg/kg), administered by intraperitoneal injection in an LPS/D-GalN-induced acute liver injury mouse model, significantly alleviated histological damage in the liver, reduced plasma levels of transaminases, and improved mouse survival rates. Luzindole also inhibited the production of pro-inflammatory cytokines TNF-α and IL-6, and the activation of caspase-3, -8, and -9, as well as the cleavage of caspase-3 and PARP, thereby attenuating LPS/D-GalN-induced hepatocyte apoptosis^[8].

References:
[1] Chan KH, Wong YH. A molecular and chemical perspective in defining melatonin receptor subtype selectivity. Int J Mol Sci. 2013 Sep 6;14(9):18385-406.
[2] Teh MT, Sugden D. Comparison of the structure-activity relationships of melatonin receptor agonists and antagonists: lengthening the N-acyl side-chain has differing effects on potency on Xenopus melanophores. Naunyn Schmiedebergs Arch Pharmacol. 1998 Nov;358(5):522-8.
[3] Gengatharan A, Malvaut S, Marymonchyk A, et al. Adult neural stem cell activation in mice is regulated by the day/night cycle and intracellular calcium dynamics. Cell. 2021 Feb 4;184(3):709-722.e13.
[4] Constantinescu CS, Hilliard B, Ventura E, et al. Luzindole, a melatonin receptor antagonist, suppresses experimental autoimmune encephalomyelitis. Pathobiology. 1997;65(4):190-4.
[5] Fan T, Pi H, Li M, et al. Inhibiting MT2-TFE3-dependent autophagy enhances melatonin-induced apoptosis in tongue squamous cell carcinoma. J Pineal Res. 2018 Mar;64(2).
[6] Kanishi Y, Kobayashi Y, Noda S, et al. Differential growth inhibitory effect of melatonin on two endometrial cancer cell lines. J Pineal Res. 2000 May;28(4):227-33.
[7] Matos RS, Oriá RB, Bruin PFC, et al. Acute blockade of endogenous melatonin by Luzindole, with or without peripheral LPS injection, induces jejunal inflammation and morphological alterations in Swiss mice. Braz J Med Biol Res. 2021 Aug 20;54(11):e11215.
[8] Luo Y, Yang Y, Shen Y, et al. Luzindole attenuates LPS/d-galactosamine-induced acute hepatitis in mice. Innate Immun. 2020 May;26(4):319-327.

Luzindole是一种选择性褪黑激素受体（MT）拮抗剂，对MT1的Ki值为158nM，对MT2的Ki值为10.2nM^[1]。Luzindole优先作用于MT2（Mel1b）受体^[2]。Luzindole可用于体外和体内评估褪黑激素受体信号在多种途径中的作用，包括昼夜节律、动物行为和黑色素细胞反应^[3]。Luzindole还可以抑制实验性自身免疫性脑脊髓炎（EAE）并具有抗抑郁作用^[4]。

在体外，Luzindole（200μM）预处理舌鳞癌Cal27细胞2小时，随后与2mM褪黑素共同孵育24小时，Luzindole阻断了褪黑素对TFE3（转录因子E3）去磷酸化和核转位的促进作用，进而抑制细胞自噬过程，同时增加了Caspase-3活性^[5]。Luzindole（10nM、100nM和100mM）预处理雌激素受体阳性的Ishikawa子宫内膜癌细胞96小时，随后与1nM褪黑素共同孵育，Luzindole完全阻断了褪黑素对细胞增殖的抑制作用^[6]。

在体内，Luzindole（0.35mg/kg）单独或与脂多糖（LPS；1.25mg/kg）联合，通过腹腔注射处理Swiss小鼠1.5小时，可诱导小肠炎症和形态学改变。Luzindole单独处理可导致绒毛高度缩短、杯状细胞数量减少，还导致非蛋白硫醇（NP-SHs）水平升高和过氧化氢酶（CAT）活性降低^[7]。Luzindole（40mg/kg）在LPS/D-GalN诱导的急性肝损伤小鼠模型中，通过腹腔注射给药，能够显著减轻肝脏组织的病理损伤，降低血浆中转氨酶（ALT和AST）的水平，并提高小鼠的生存率。Luzindole还抑制了促炎细胞因子TNF-α和IL-6的产生，抑制了caspase-3、-8和-9的激活以及caspase-3和PARP的裂解，减轻LPS/D-GalN诱导的肝细胞凋亡^[8]。