SR 144528 is a highly potent, selective, and orally active antagonist for the CB2 receptor, with a Ki value of 0.6nM [1]. SR 144528 inhibited microsomal ACAT activity in vitro, with an IC50 value of 3.6±1.1μM[2]. SR 144528 has been used for comparative analyses of biased signaling and off-target activity of CB2 receptor ligands[3].
In vitro, SR 144528 pretreatment at 2μM for 1h inhibited apoptosis of Raw 264.7 macrophages following a 16h treatment with 7-ketocholesterol (7KC)[2]. Pretreatment of microglia with 1µM SR 144528 for 15min significantly reduced LPS/IFN-γ (16h)-induced secretion of TNF-α, IL-6, and CCL2, as well as microglial activation[4]. Pretreatment of eosinophilic Eol-1 cells with 10µM SR 144528 for 30min significantly reduced OEA-induced (24h) activation and decreased the mRNA expression of IL-1β, IL-8, IL-5, and IL-13[5].
In vivo, a single dose of SR 144528 (1mg/kg) administered intraperitoneally to male Wistar rats for 30min enhances WIN 55,212-2 (5mg/kg; 24h; i.p.)-induced gastrointestinal motility and gastric emptying[6]. A single intraperitoneal injection of 0.1mg/kg SR 144528 at 30min resulted in a significant reduction in μ-opioid receptor (MOR) mRNA expression in the brains of both CB1 wild-type (CB1+/+) and CB1 cannabinoid receptor knockout mice (CB1−/−) [7]. Intraperitoneal injection of SR 144528 (1mg/kg/day) to C57BL/6J mice once daily for 1 week increased cued fear memory without contextual fear memory[8].
References:
[1] Rinaldi-Carmona M, Barth F, Millan J, et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor[J]. The Journal of pharmacology and experimental therapeutics, 1998, 284(2): 644-650.
[2] Thewke D, Freeman-Anderson N, Pickle T, et al. AM-251 and SR144528 are acyl CoA: cholesterol acyltransferase inhibitors[J]. Biochemical and biophysical research communications, 2009, 381(2): 181-186.
[3] Soethoudt M, Grether U, Fingerle J, et al. Cannabinoid CB2 receptor ligand profiling reveals biased signalling and off-target activity[J]. Nature communications, 2017, 8(1): 13958.
[4] Olabiyi B F, Schmoele A C, Beins E C, et al. Pharmacological blockade of cannabinoid receptor 2 signaling does not affect LPS/IFN-γ-induced microglial activation[J]. Scientific Reports, 2023, 13(1): 11105.
[5] Kwon E K, Choi Y, Sim S, et al. Cannabinoid receptor 2 as a regulator of inflammation induced oleoylethanolamide in eosinophilic asthma[J]. Journal of Allergy and Clinical Immunology, 2024, 153(4): 998-1009. e9.
[6] Abalo R, Cabezos P A, Vera G, et al. The cannabinoid antagonist SR144528 enhances the acute effect of WIN 55,212‐2 on gastrointestinal motility in the rat[J]. Neurogastroenterology & Motility, 2010, 22(6): 694-e206.
[7] Páldy E, Bereczki E, Sántha M, et al. CB2 cannabinoid receptor antagonist SR144528 decreases mu-opioid receptor expression and activation in mouse brainstem: role of CB2 receptor in pain[J]. Neurochemistry international, 2008, 53(6-8): 309-316.
[8] Duphare C, Li Y, Kim J. Roles for Type‐2 Cannabinoid Receptors in the Retrieval and Retention of Fear Memory in Mice[J]. The FASEB Journal, 2017, 31: 988.10-988.10.
SR 144528是一种高效、选择性且具有口服活性的CB2受体拮抗剂，对CB2受体的Ki值为0.6nM[1]。SR 144528能在体外抑制微粒体ACAT活性，IC50值为3.6±1.1μM[2]。SR 144528已被用于CB2受体配体的偏向信号传导和脱靶活性的比较分析[3]。
在体外，用2μM的SR 144528预处理Raw 264.7巨噬细胞1小时，能够抑制随后由7-酮胆固醇（7KC）处理16小时所诱导的细胞凋亡[2]。用1µM的SR 144528预处理小胶质细胞15分钟，能显著减少LPS/IFN-γ（处理16小时）诱导的TNF-α、IL-6和CCL2的分泌，并抑制小胶质细胞的活化[4]。用10µM的SR 144528预处理嗜酸性Eol-1细胞30分钟，可显著减弱OEA（处理24小时）诱导的细胞活化，并降低IL-1β、IL-8、IL-5和IL-13的mRNA表达水平[5]。
在体内，向雄性Wistar大鼠单次腹腔注射SR 144528（1mg/kg）30分钟后，能增强WIN 55,212-2（5mg/kg；处理 24 小时；腹腔注射）诱导的胃肠动力和胃排空作用[6]。向CB1野生型（CB1+/+）和CB1大麻素受体基因敲除小鼠（CB1−/−）单次腹腔注射0.1mg/kg剂量的SR 144528 30分钟后，可导致大脑中 μ-阿片受体（MOR） mRNA 表达显著降低 [7]。向C57BL/6J 小鼠每天一次腹腔注射SR 144528（1mg/kg/day），连续一周，能增强线索性恐惧记忆，不影响情境性恐惧记忆[8]。