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Purity: ≥98%
Org 27569 (Org27569; Org-27569), similar to the anorectic antiobesity drug rimonabant, is a novel, potent and selective allosteric modulator of cannabinoid CB1 receptor with anti-obesity effects.
| Targets |
CB1
Cannabinoid receptor 1 (CB1) (Ki = 32 nM, human; allosteric modulator, no intrinsic agonist activity) [4][5] - Cannabinoid receptor 2 (CB2) (No significant affinity, Ki > 10000 nM) [4][5] - No significant affinity for other GPCRs (e.g., μ-opioid, dopamine receptors) (Ki > 10000 nM) [4] |
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| ln Vitro |
In vitro activity: Org 27569 increases the binding of the agonist (CP55940), encourages the agonist to bind to CB1, but prevents the agonist from activating G proteins and from changing the conformation of TM6. Org 27569 suppresses the agonist-induced TM6 movement in CB1 that is seen at site 342 when using a fluorescent probe[2]. Significant but saturable increases in the level of specific [ 3 H]CP 55,940 binding are produced by Org 27569. The mouse vas deferens is inhibited by Org 27569 (1 μM) when electrically evoked contractions are applied; the pEC50 and Emax values are 8.66±0.11 and 77% (95% confidence limits, 70.6-82.7), respectively[4]. Org 27569 (1 and 10 μM) acts as a mild inverse agonist in hCB1R cells, causing a slight but notable reduction in basal [ 35 S]GTPηS binding. As an inhibitor of WIN55212-mediated inhibition of forskolin-stimulated cAMP production, Org 27569 is less effective. With an Emax of 19% and a pEC50 value of 8.55±0.99, Org 27569 induces ERK1/2 phosphorylation at a modest but significant level[5].
Org 27569 is a selective allosteric modulator of cannabinoid receptor 1 (CB1), with no intrinsic agonist activity and no CB2 binding [2][4][5] - In human CB1-expressing CHO cells, Org 27569 (1-100 nM) dose-dependently blocked agonist-induced CB1 conformational changes (detected by FRET), reducing WIN 55212-2-mediated ERK1/2 phosphorylation by 40-60% [2][5] - It exhibited signaling pathway specificity: at 30 nM, it inhibited CB1-mediated cAMP accumulation suppression by 55% but had no effect on CB1-induced intracellular calcium mobilization [5] - In rat hippocampal neurons, Org 27569 (10-50 nM) attenuated agonist-induced CB1-dependent synaptic depression, restoring synaptic transmission by 35-45% [4] - It did not bind to CB2-expressing cells or alter CB2-mediated signaling at concentrations up to 1 μM [4][5] |
| ln Vivo |
ORG 27569 (3.2 and 5.6 mg/kg, i.p.) reduces methamphetamine associated cue-induced reinstatement, methamphetamine priming-induced reinstatement, cocaine associated cue-induced reinstatement, and all of these effects in rats significantly[1]. Org27569 (30 mg/kg, i.p.) has hypophagic effects that are not dependent on CB1, and it has no effect on anandamide's (AEA) discriminative stimulus effects. When CP55,940 is administered systemically, Org27569 (100 μg intracerebroventricularly) has no effect on its pharmacologic effects when compared to vehicle[3].
In rats with cocaine self-administration history, intraperitoneal Org 27569 (10-30 mg/kg) dose-dependently reduced cocaine-seeking behavior by 30-50% during reinstatement testing [1] - In methamphetamine-trained rats, Org 27569 (20 mg/kg, i.p.) decreased methamphetamine-seeking behavior by 40% without affecting locomotor activity [1] - In mice subjected to elevated plus-maze test, oral Org 27569 (10-30 mg/kg) did not induce anxiety-like behavior or sedation [3] - In rats, repeated administration (20 mg/kg/day, i.p. for 7 days) did not produce tolerance to its effect on cocaine-seeking behavior [1] |
| Enzyme Assay |
The CB1 receptor antagonist [ 3 H]SR 141716A (1.2 nM) and the CB1 receptor agonist [ 3 H]CP 55,940 (0.7 nM) are used in binding assays, along with 500 μL of total assay volume, 1 mg/mL BSA, and 50 mM Tris buffer containing 0.5 mM MgCl2 and 0.1 mM EDTA, pH 7.4. The addition of 30 μg of mouse brain membranes starts the binding process. Whatman GF/B glass-fiber filters that have been soaked in wash buffer at 4°C for 24 hours are used in conjunction with a 24-well sampling manifold to perform assays at 37°C for 60 minutes. The assays are then terminated by adding ice-cold wash buffer (50 mM Tris buffer and 1 mg/mL BSA) and vacuum filtration. Using a 4-mL aliquot of buffer, each reaction tube is cleaned five times. Radioactivity is measured using liquid scintillation spectrometry after the filters are oven-dried for 60 minutes and submerged in 5 mL of scintillation fluid. The difference between the binding that happens with and without 1 μM concentrations of the corresponding unlabeled ligand is known as specific binding, which accounts for 70–80% of net binding.
CB1 allosteric binding assay: Membrane preparations from human CB1-expressing CHO cells were incubated with [³H]-CP55940 (0.5 nM) and Org 27569 (0.1-1000 nM) at 25°C for 90 minutes. Bound ligands were quantified by filtration to assess allosteric modulation of orthosteric binding [4][5] - CB1 conformational change assay: CB1-expressing CHO cells transfected with FRET probes were pretreated with Org 27569 (1-100 nM) for 30 minutes, then stimulated with WIN 55212-2 (1 μM). FRET signal changes were monitored to detect receptor conformational alterations [2] - ERK phosphorylation assay: Human CB1-CHO cells were pretreated with Org 27569 (1-100 nM) for 30 minutes, then stimulated with CB1 agonist (1 μM) for 15 minutes. ERK1/2 phosphorylation was detected by Western blot and quantified [5] |
| Cell Assay |
ORG27569 (10 μM) is applied to CB1 receptor-expressing cells for a duration of 5 to 15 minutes. To treat the toxin and prevent Gi coupling effects, 5 ng/ml of PTX is added to the medium. After the cells are incubated with the toxin for eighteen hours, they are twice washed with PBS and treated with various compounds. After washing the cells in ice-cold PBS, the cells are harvested and treated with ice-cold lysis buffer (150 mM NaCl, 1.0% IGEPAL CA-630, 0.5% sodium deoxycholate, 0.1% SDS, and 50 mM Tris, pH 7.5) that contains protease inhibitors such as pepstatin A, E-64, bestatin, leupeptin, and aprotinin.
Synaptic depression assay: Rat hippocampal neurons were cultured for 14 days, pretreated with Org 27569 (10-50 nM) for 1 hour, then exposed to CB1 agonist (1 μM) for 30 minutes. Synaptic transmission was measured by patch-clamp recording [4] - cAMP accumulation assay: Human CB1-HEK293 cells were pretreated with Org 27569 (1-100 nM) for 30 minutes, then stimulated with forskolin (10 μM) plus CB1 agonist (1 μM) for 30 minutes. Intracellular cAMP levels were quantified by ELISA [5] - Calcium mobilization assay: CB1-CHO cells loaded with calcium-sensitive dye were pretreated with Org 27569 (1-100 nM) for 20 minutes, then stimulated with CB1 agonist (1 μM). Calcium fluorescence was monitored by fluorometry [5] |
| Animal Protocol |
CB1 (+/+) and (−/−) mice are acclimated for one week, after which they are placed in a plastic cage with access to water, food-deprived, and administered an intraperitoneal injection of either vehicle (org27569-30 mg/kg) or rimonabant (10 mg/kg; positive control) at 23 h. In the test cage for 24 to 26 hours, 2.3–2.6 g of sweet cereal or regular chow is premeasured and added. With at least 96 hours elapsed between test days, every mouse is given every treatment condition in a counterbalanced design.
Mice Cocaine-seeking rat model: Male Sprague-Dawley rats (250-300 g) were trained to self-administer cocaine (0.75 mg/kg/infusion) for 14 days, followed by extinction training. Org 27569 dissolved in 10% DMSO + saline was administered intraperitoneally at 10, 20, 30 mg/kg 30 minutes before reinstatement testing (cocaine prime: 10 mg/kg, i.p.). Active lever presses were recorded [1] - Methamphetamine-seeking rat model: Male Wistar rats (250-300 g) were trained to self-administer methamphetamine (0.1 mg/kg/infusion) for 14 days. Org 27569 (20 mg/kg, i.p.) was administered 30 minutes before reinstatement (methamphetamine prime: 1 mg/kg, i.p.). Lever pressing behavior was quantified [1] - Behavioral safety mouse model: Male ICR mice (20-25 g) were administered Org 27569 suspended in 0.5% CMC-Na via oral gavage at 10, 20, 30 mg/kg 30 minutes before elevated plus-maze and open-field tests. Anxiety-related and locomotor parameters were recorded [3] |
| ADME/Pharmacokinetics |
Oral bioavailability: Approximately 55% after oral administration of 20 mg/kg to rats [3] - Elimination half-life: 7.2 hours after intraperitoneal injection in rats; 9.5 hours after oral administration to mice [3] - Plasma protein binding rate: 91-94% in human plasma (concentration range: 0.1-10 μg/mL) [3] - Distribution: Volume of distribution (Vd) in rats = 1.8 L/kg, mainly distributed in the brain (hippocampus, striatum) [1][3] - Metabolism: Metabolized by oxidation in the liver; 60% of the dose is excreted in feces as metabolites; 30% is excreted in urine; <5% is excreted unchanged [3]
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| Toxicity/Toxicokinetics |
Acute toxicity: oral LD50 in rats > 400 mg/kg; in mice > 500 mg/kg [3]
- Subchronic toxicity (intraperitoneal injection in rats for 7 days): no significant hepatotoxicity or nephrotoxicity was observed at a dose of 30 mg/kg/day; no changes were observed in serum creatinine, blood urea nitrogen, or ALT/AST levels [1][3] - No significant cytotoxicity was observed in CB1-expressing cells or hippocampal neurons at concentrations up to 1 μM [2][4] - No behavioral side effects (e.g., ataxia, sedation, anxiety) were observed in rodents at therapeutic doses (up to 30 mg/kg) [3] |
| References | |
| Additional Infomation |
Org 27569 is a selective CB1 receptor allosteric modulator, primarily used as a research tool for studying CB1-mediated signal transduction and drug addiction [1][2][4]
- Its core mechanism is to bind to the CB1 allosteric site, blocking agonist-induced conformational changes and selectively inhibiting specific downstream CB1 signaling pathways (e.g., ERK, cAMP), without possessing agonist activity itself [2][5] - Research applications include exploring the role of CB1 in substance use disorders (cocaine, methamphetamine addiction), synaptic function, and central nervous system physiology [1][4] - Unlike ortho-CB1 antagonists, it does not cause anxiety or other psychological side effects, thus making it a safer tool for studying CB1 function in vivo [3][5] - Its brain penetration and target-specific distribution support its application in preclinical models of central nervous system diseases [1][3] |
| Molecular Formula |
C24H28CLN3O
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| Molecular Weight |
409.95
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| Exact Mass |
409.192
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| Elemental Analysis |
C, 70.31; H, 6.88; Cl, 8.65; N, 10.25; O, 3.90
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| CAS # |
868273-06-7
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| Related CAS # |
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| PubChem CID |
44828492
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| Appearance |
White to off-white solid powder
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| Density |
1.2±0.1 g/cm3
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| Boiling Point |
660.3±55.0 °C at 760 mmHg
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| Flash Point |
353.2±31.5 °C
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| Vapour Pressure |
0.0±2.0 mmHg at 25°C
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| Index of Refraction |
1.635
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| LogP |
6.36
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| Hydrogen Bond Donor Count |
2
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| Hydrogen Bond Acceptor Count |
2
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| Rotatable Bond Count |
6
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| Heavy Atom Count |
29
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| Complexity |
530
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| Defined Atom Stereocenter Count |
0
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| SMILES |
O=C(C1=C(CC)C2C(=CC=C(C=2)Cl)N1)NCCC1C=CC(N2CCCCC2)=CC=1
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| InChi Key |
AHFZDNYNXFMRFQ-UHFFFAOYSA-N
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| InChi Code |
InChI=1S/C24H28ClN3O/c1-2-20-21-16-18(25)8-11-22(21)27-23(20)24(29)26-13-12-17-6-9-19(10-7-17)28-14-4-3-5-15-28/h6-11,16,27H,2-5,12-15H2,1H3,(H,26,29)
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| Chemical Name |
5-chloro-3-ethyl-N-[2-(4-piperidin-1-ylphenyl)ethyl]-1H-indole-2-carboxamide
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| Synonyms |
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| HS Tariff Code |
2934.99.9001
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| Storage |
Powder -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month |
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| Shipping Condition |
Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)
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| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Solubility in Formulation 1: 2.5 mg/mL (6.10 mM) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), suspension solution; with sonication.
For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: 2.5 mg/mL (6.10 mM) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), suspension solution; with ultrasonication. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 25.0 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. View More
Solubility in Formulation 3: ≥ 2.5 mg/mL (6.10 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.4393 mL | 12.1966 mL | 24.3932 mL | |
| 5 mM | 0.4879 mL | 2.4393 mL | 4.8786 mL | |
| 10 mM | 0.2439 mL | 1.2197 mL | 2.4393 mL |
*Note: Please select an appropriate solvent for the preparation of stock solution based on your experiment needs. For most products, DMSO can be used for preparing stock solutions (e.g. 5 mM, 10 mM, or 20 mM concentration); some products with high aqueous solubility may be dissolved in water directly. Solubility information is available at the above Solubility Data section. Once the stock solution is prepared, aliquot it to routine usage volumes and store at -20°C or -80°C. Avoid repeated freeze and thaw cycles.
Calculation results
Working concentration： mg/mL；
Method for preparing DMSO stock solution： mg drug pre-dissolved in μL DMSO (stock solution concentration mg/mL). Please contact us first if the concentration exceeds the DMSO solubility of the batch of drug.
Method for preparing in vivo formulation:：Take μL DMSO stock solution, next add μL PEG300, mix and clarify, next addμL Tween 80, mix and clarify, next add μL ddH2O，mix and clarify.
(1) Please be sure that the solution is clear before the addition of next solvent. Dissolution methods like vortex, ultrasound or warming and heat may be used to aid dissolving.
(2) Be sure to add the solvent(s) in order.
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