Org 27569 is a potent CB1 receptor allosteric modulator (pEC50 = 8.24). Org 27569 inhibits CB1 receptor antagonist efficacy in vitro (pKb = 7.57). Org 27569 binds to a regulatory site on the CB1 receptor target, causing a conformational change that increases the binding affinity of CB1 agonists such as CP 55,940, while decreasing the binding affinity of CB1 antagonists or inverse agonists such as rimonabant. Org 27569 significantly increases binding of the CB1 agonist [3H]CP 55.940 (pKb = 5.67) and decreases binding of the CB1 inverse agonist [3H]SR 141716A (pKb = 5.95), and so in practice behaves as an insurmountable antagonist of CB1 receptor function.
|Cell lines||HEK293 cells expressing the wild-type (●), T210I (△), and T210A (■) receptors|
|Preparation method||GTPγS Binding Assay
15 μg of membranes were incubated for 60 min at 30 °C in a total volume of 500 μM GTPγS binding assay buffer (50 mM Tris-HCl, pH 7.4, 3 mM MgCl2, 0.2 mM EGTA, and 100 mM NaCl) with unlabeled ligand (at least nine different concentrations were used ranging between 100 pM and 100 μM), 0.1 nM [35S]GTPγS (1250 Ci/mmol; PerkinElmer Life Sciences), 10 μM GDP, and 0.1% (w/v) BSA. The basal GTPγS binding was measured in the absence of ligand. Nonspecific binding was determined with 10 μM unlabeled GTPγS (Sigma). The reaction was terminated by rapid filtration through Whatman GF/C filters. The radioactivity trapped in the filters was determined by liquid scintillation counting.
|Concentrations||0~10 μ M|
|Incubation time||5~15 min|
|Animal models||Adult male Sprague–Dawley rats|
|Formulation||a mixture of 1 part absolute ethanol, 1 part Emulphor-620 (Rhodia Inc., Cranbury, NJ), and 18 parts physiological saline|
|Dosages||8 days of daily 5.6 mg/kg|
|Body Surface Area (m2)||0.007||0.025||0.15||0.05||0.02||0.5|
|Animal A (mg/kg) = Animal B (mg/kg) multiplied by||Animal B Km|
|Animal A Km|
For example, to modify the dose of resveratrol used for a mouse (22.4 mg/kg) to a dose based on the BSA for a rat, multiply 22.4 mg/kg by the Km factor for a mouse and then divide by the Km factor for a rat. This calculation results in a rat equivalent dose for resveratrol of 11.2 mg/kg.
Behavioral effects of the cannabinoid CB1 receptor allosteric modulator ORG27569 in rats.
Ding Y, et al. Pharmacol Res Perspect. 2014 Dec;2(6):e00069. PMID: 25431655.
Allosteric modulator ORG27569 induces CB1 cannabinoid receptor high affinity agonist binding state, receptor internalization, and Gi protein-independent ERK1/2 kinase activation.
Ahn KH, et al. J Biol Chem. 2012 Apr 6;287(15):12070-82. PMID: 22343625.
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