A CB1 receptor antagonist
AM521 is a potent cannabinoid 1 (CB1) receptor antagonist with IC50 of 8 nM and Ki of 7.49 nM.
The cannabinoid receptor (CB1 and CB2) is a member of G-protein coupled receptor which plays a significant role in physiologic processes such as cognitive and immune functions.
AM251 inhibited the coupling of cannabinoid 1 receptor agonists and antagonists onto the rat brain membranes [1]. In hippocampus, 2 μm AM 251 reduced the endocannabinoids inhibitory effects on GABA release [2]. 1 μm AM 251 inhibited endocannabinoid-signaled depression of interneuron firing [3]. AM251 reduced neuronal excitability and inhibited excitatory and inhibitory transmitter release via inhibition of voltage-dependent Na+ channels [4].
AM251 caused sustained anorectic effect in rat for obesity treatment [5]. AM251 may also disrupt the training – induced increase of hippocampus cannabinoids level that promotes memory consolidation [6].
参考文献:
[1] Lan, R, Q.? Liu, P. Fan, S. Lin, S. R. Fernando, D. McCallion, R. Pertwee & A. Makriyannis: Structure-activity relationships of pyrazole derivatives as cannabinoid receptor antagonists. J. Med. Chem. 1999, 42, 769–776.
[2] Willow, M.? & W. A. Catterall: Inhibition of binding of [3H]batrachotoxin A 20-α-benzoate to sodium channels by the anticonvulsant drugs diphenylhydantoin and carbamazepine. Mol. Pharmacol. 1982, 22, 627–635.
[3] Kreitzer, A.? C., A. G. Carter & W. G. Regehr: Inhibition of interneuron firing extends the spread of endocannabinoid signaling in the cerebellum. Neuron 2002, 34, 787–796.
[4] Liao C, Zheng J, David LS, Nicholson RA.? Inhibition of voltage-sensitive sodium channels by the cannabinoid 1 receptor antagonist AM 251 in mammalian brain.? Basic Clin Pharmacol Toxicol. 2004 Feb;94(2):73-8.
[5] Chambers AP, Sharkey KA, Koopmans HS.? Cannabinoid (CB)1 receptor antagonist, AM 251, causes a sustained reduction of daily food intake in the rat.? Physiol Behav.? 2004 Oct 15;82(5):863-9.
[6] de Oliveira Alvares L, de Oliveira LF, Camboim C, Diehl F, Genro BP, Lanziotti VB, Quillfeldt JA.? Amnestic effect of intrahippocampal AM251, a CB1-selective blocker, in the inhibitory avoidance, but not in the open field habituation task, in rats.? Neurobiol Learn Mem. 2005 Mar;83(2):119-24.
| Kinase experiment [1]: | |
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Caspase-3 assay |
Macrophages are seeded (2 × 106/well) in 12-well culture plates. AM-251 are added from 4 mM stock solutions prepared in DMSO, 1 hour prior to the addition of 7-ketocholesterol from a 2 mg/mL ethanol stock solution. Controls are adjusted to receive equivalent volumes of DMSO and ethanol. After 16 hours, caspase-3 activity is determined. All treatments are done in triplicate and the data presented as the mean RFLU/mg protein± SD. |
| Cell experiment [2, 3]: | |
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Cell lines |
A375 human melanoma cells; Raw 264.7 macrophages |
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Preparation method |
The solubility of this compound in DMSO is >10 mM. General tips for obtaining a higher concentration: Please warm the tube at 37℃ for 10 minutes and/or shake it in the ultrasonic bath for a while. Stock solution can be stored below -20℃ for several months. |
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Reacting condition |
5 μM for 48 h and 72 h; or 0.5, 2 μM for 16 h |
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Applications |
Treatment with AM251 (5 μmol/l) induced apoptosis, G2/M cell cycle arrest, and cAMP increase in A375 human melanoma cells. Moreover, AM-251 inhibited 7-ketocholesterol induced apoptosis of Raw 264.7 macrophages. |
| Animal experiment [3]: | |
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Animal models |
Adult male Sprague-Dawley rats model |
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Dosage form |
3 mg/kg, i.p., for 1-4 h |
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Applications |
AM251 increased paraoxon and chlorpyrifos oxon toxicity in rats. Moreover, AM-251 (1-4 μM) inhibited sterol esterification in vivo. AM-251 inhibited acetylated LDL-stimulated cholesterol esterification in resident peritoneal macrophages from wild type and CB2 null mice. |
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Other notes |
Please test the solubility of all compounds indoor, and the actual solubility may slightly differ with the theoretical value. This is caused by an experimental system error and it is normal. |
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参考文献: 1. Thewke, D., Freeman-Anderson, N., Pickle, T., Netherland, C. and Chilton, C. (2009) AM-251 and SR144528 are acyl CoA:cholesterol acyltransferase inhibitors. Biochem Biophys Res Commun. 381, 181-186 2. Carpi, S., Fogli, S., Romanini, A., Pellegrino, M., Adinolfi, B., Podesta, A., Costa, B., Da Pozzo, E., Martini, C., Breschi, M. C. and Nieri, P. (2015) AM251 induces apoptosis and G2/M cell cycle arrest in A375 human melanoma cells. Anticancer Drugs. 26, 754-762 3. Liu, J. and Pope, C. (2015) The cannabinoid receptor antagonist AM251 increases paraoxon and chlorpyrifos oxon toxicity in rats. Neurotoxicology. 46, 12-18 |
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