AM 281 is a high-affinity and selective CB2 receptor antagonist with an IC50 of 13μM[1]. AM 281 is used to study the role of the endocannabinoid system in various physiological and pathological processes and has potential applications in the research of inflammation, pain, and neurodegenerative diseases[2]. AM 281 selectively activates the CB2 receptor, which is mainly expressed in immune cells and peripheral tissues, while having minimal activation of the CB1 receptor expressed in the central nervous system[3]. AM 281 has been shown to modulate immune responses and has potential therapeutic applications in diseases related to the endocannabinoid system[4].
In vitro, AM 281 (2μM) was used to pre-treat myocardial HL-1 cells for 30 minutes, followed by co-incubation with quetiapine (Que, 2μM) for 24 hours. AM 281 significantly reduced quetiapine-induced myocardial cell damage. AM 281 inhibited the activation of necroptosis by reducing the protein levels of RIP3 and MLKL and inhibiting the phosphorylation of MLKL in myocardial cells. Additionally, AM 281 significantly decreased inflammation and fibrosis in myocardial cells, improving their pathological state[5]. AM 281 (1, 2, and 4μmol/L) was used to pre-treat rat embryonic ventricular myocardial-derived H9c2 cells for 2 hours, followed by co-incubation with doxorubicin (DOX, 1 or 5μM) for 18 hours. AM 281 significantly increased cell viability and inhibited DOX-induced DNA damage and apoptosis[6].
In vivo, AM 281 (0.62, 1.25, and 2.5mg/kg) was administered via intraperitoneal injection to mice that had been treated with morphine (30-90mg/kg) for 3 consecutive days. AM 281 (2.5mg/kg) significantly improved the recognition index (RI) and alleviated memory deficits in mice undergoing spontaneous morphine withdrawal by inhibiting the activation of CB1 receptors[7]. AM 281 (1, 2, and 4mg/kg) was administered via intraperitoneal injection 30 minutes before the first re-exposure to the aversive context in mice. The results showed that AM 281 at a dose of 1mg/kg significantly increased freezing behavior (fear response) in mice[8].
References:
[1] Kadoi Y, Hinohara H, Kunimoto F, et al. Cannabinoid antagonist AM 281 reduces mortality rate and neurologic dysfunction after cecal ligation and puncture in rats. Crit Care Med. 2005 Nov;33(11):2629-36.
[2] Droste SM, Saland SK, Schlitter EK, et al. AM 251 differentially effects food-maintained responding depending on food palatability. Pharmacol Biochem Behav. 2010 Jun;95(4):443-8.
[3] Rutkowska M, Jamontt J, Gliniak H. Effects of cannabinoids on the anxiety-like response in mice. Pharmacol Rep. 2006 Mar-Apr;58(2):200-6.
[4] Gifford AN, Bruneus M, Gatley SJ, et al. Large receptor reserve for cannabinoid actions in the central nervous system. J Pharmacol Exp Ther. 1999 Feb;288(2):478-83.
[5] Li X, Peng Z, Zhou Y, Wang J, et al. Quetiapine induces myocardial necroptotic cell death through bidirectional regulation of cannabinoid receptors. Toxicol Lett. 2019 Oct 1;313:77-90.
[6] Mukhopadhyay P, Bátkai S, Rajesh M, et al. Pharmacological inhibition of CB1 cannabinoid receptor protects against doxorubicin-induced cardiotoxicity. J Am Coll Cardiol. 2007 Aug 7;50(6):528-36.
[7] Vaseghi G, Rabbani M, Hajhashemi V. The effect of AM281, a cannabinoid antagonist, on memory performance during spontaneous morphine withdrawal in mice. Res Pharm Sci. 2013 Jan;8(1):59-64.
[8] Lisboa SF, Gomes FV, Silva AL, et al. Increased Contextual Fear Conditioning in iNOS Knockout Mice: Additional Evidence for the Involvement of Nitric Oxide in Stress-Related Disorders and Contribution of the Endocannabinoid System. Int J Neuropsychopharmacol. 2015 Jan 24;18(8):pyv005.
AM 281是一种高亲和力和特异性的选择性CB2受体拮抗剂，其IC50为13μM[1]。AM 281用于研究内源性大麻素系统在各种生理和病理过程中的作用，具有在炎症、疼痛和神经退行性疾病研究中的潜在应用价值[2]。AM 281能够选择性地激活主要表达于免疫细胞和外周组织的CB2受体，而对中枢神经系统中表达的CB1受体激活作用较弱[3]。AM 281已被证明可以调节免疫反应，并在内源性大麻素系统相关的疾病中具有潜在的治疗应用价值[4]。
在体外，AM 281（2μM）预处理心肌HL-1细胞30分钟，随后与喹硫平（Que，2μM）共孵育24小时，AM 281显著减轻了喹硫平诱导的心肌细胞损伤。AM 281通过抑制CB1R，减少了心肌细胞中RIP3和MLKL的蛋白水平，并抑制了MLKL的磷酸化，从而阻断了细胞坏死样凋亡（necroptosis）的激活过程。此外，AM 281还显著降低了心肌细胞的炎症反应和纤维化程度，改善了心肌细胞的病理状态[5]。AM 281（1、2、4μmol/L）预处理大鼠胚胎心室肌源性H9c2细胞2小时，随后与多柔比星（DOX，1或5μM）共孵育18小时，AM 281显著提高了细胞的存活率，抑制了DOX诱导的DNA损伤和细胞凋亡[6]。
在体内，AM 281（0.62、1.25和2.5mg/kg）通过腹腔注射治疗接受吗啡（30-90mg/kg）给药的小鼠，连续3天。AM 281（2.5mg/kg）显著改善了记忆识别指数（RI），AM 281通过抑制CB1受体的激活，减轻了自发吗啡戒断引起的小鼠记忆障碍[7]。AM 281在（1、2和4mg/kg）通过腹腔注射给药后30分钟，对小鼠进行第一次对恐惧环境的再暴露。结果显示，AM 281在1mg/kg剂量下显著增加了小鼠的冻结行为（恐惧反应）[8]。