LP-211 is a selective, blood-brain barrier-permeable 5-HT7 receptor agonist (Ki=0.58nM) with higher selectivity over the 5-HT1A receptor (Ki=188nM) and the D2 receptor (Ki=142nM)[1-2]. LP-211 can modulate histone H3 acetylation levels and influence the association of the MeCP2 co-repressor protein by activating the 5-HT7 receptor. LP-211 can be used in research related to neurodevelopmental disorders such as Rett syndrome and Fragile X syndrome, as well as neuropathic pain and memory impairment[3-4].
In vitro, LP-211 (10µM) stimulated THP-1-derived macrophages for 48 hours. LP-211 significantly reduced the phagocytic and migratory capacity of pro-inflammatory M1-like macrophages, while also altering the cytokine and chemokine secretion profiles of all macrophage types (M0, M1, M2a, M2c)[5]. LP-211 (1µM) was incubated with mitochondria purified from human SH-SY5Y neuroblastoma cells for 3 minutes. LP-211 did not significantly affect the activity of mitochondrial respiratory chain cytochrome c oxidas[6].
In vivo, a single intraperitoneal injection of LP-211 (3mg/kg) was administered to male Fmr1-KO (B6.129P2-Fmr1tm1Cgr/J) mice, 30 minutes prior to behavioral testing. LP-211 significantly reduced the duration of their self-grooming behavior[7]. Single intraperitoneal injection of LP-211 (10mg/kg) was administered to adult male C57BL/6 mice 7-10 days after chronic constriction injury (CCI) surgery. The effects began 30 minutes post-injection and peaked between 90-150 minutes. LP-211 significantly increased the mechanical withdrawal threshold of the injured hind paw and completely blocked the place preference shift induced by noxious stimulation in the place escape/avoidance paradigm[8].
References:
[1] Leopoldo M, Lacivita E, De Giorgio P, et al. Structural modifications of N-(1,2,3,4-tetrahydronaphthalen-1-yl)-4-aryl-1-piperazinehexanamides: influence on lipophilicity and 5-HT7 receptor activity. Part III. J Med Chem. 2008 Sep 25;51(18):5813-22.
[2] Beaudet G, Paizanis E, Zoratto F, et al. LP-211, a selective 5-HT7 receptor agonist, increases novelty-preference and promotes risk-prone behavior in rats. Synapse. 2017 Dec;71(12).
[3] Norouzi-Javidan A, Javanbakht J, Barati F, et al. Effect of 5-HT7 receptor agonist, LP-211, on micturition following spinal cord injury in male rats. Am J Transl Res. 2016 Jun 15;8(6):2525-33.
[4] Rahdar M, Davoudi S, Dehghan S, et al. Reversal of electrophysiological and behavioral deficits mediated by 5-HT7 receptor upregulation following LP-211 treatment in an autistic-like rat model induced by prenatal valproic acid exposure. Neuropharmacology. 2024 Oct 1;257:110057.
[5] Bahr FS, Müller FE, Kasten M, et al. Serotonin receptor 5-HT7 modulates inflammatory-associated functions of macrophages. Cell Mol Life Sci. 2025 Jan 21;82(1):51.
[6] Tempio A, Niso M, Laera L, et al. Mitochondrial Membranes of Human SH-SY5Y Neuroblastoma Cells Express Serotonin 5-HT7 Receptor. Int J Mol Sci. 2020 Dec 17;21(24):9629.
[7] Sharghi S, Flunkert S, Daurer M, et al. Evaluating the effect of R-Baclofen and LP-211 on autistic behavior of the BTBR and Fmr1-KO mouse models. Front Neurosci. 2023 Mar 30;17:1087788.
[8] Santello M, Bisco A, Nevian NE, et al. The brain-penetrant 5-HT7 receptor agonist LP-211 reduces the sensory and affective components of neuropathic pain. Neurobiol Dis. 2017 Oct;106:214-221.
LP-211是一种选择性的、可透过血脑屏障的5-HT7受体（Ki=0.58nM）激动剂，选择性高于5-HT1A受体（Ki=188nM）和D2受体（Ki=142nM）[1-2]。LP-211可通过激活5-HT7受体来调节组蛋白H3乙酰化水平并影响MeCP2共抑制蛋白的关联。LP-211可用于雷特综合征、脆性X综合征等神经发育障碍以及神经病理性疼痛和记忆障碍的相关研究[3-4]。
在体外，LP-211（10μM）刺激THP-1衍生的巨噬细胞48小时。LP-211可显著降低促炎性M1样巨噬细胞的吞噬能力和迁移能力，同时改变所有巨噬细胞类型（M0、M1、M2a、M2c）的细胞因子与趋化因子分泌特性[5]。LP-211（1μM）孵育从人SH-SY5Y神经母细胞瘤细胞中纯化的线粒体3分钟。LP-211对线粒体呼吸链细胞色素c氧化酶的活性无显著影响[6]。
在体内，LP-211（3mg/kg）在行为测试前30分钟对雄性Fmr1-KO（B6.129P2-Fmr1tm1Cgr/J）小鼠进行单次腹腔注射，可显著减少其自我梳理行为的持续时间[7]。LP-211（10mg/kg）对接受慢性坐骨神经压迫损伤（CCI）手术7-10天后的成年C57BL/6雄性小鼠进行单次腹腔注射，在注射后30分钟起效，并于90-150分钟达到峰值。LP-211可显著提高受伤后爪的机械撤退阈值，并完全阻断在位置逃避/回避范式中由伤害性刺激引起的位置偏好转换[8]。