Description
SR 144528 is a cannabinoid (CB) receptor 2 inverse agonist with K
i values ranging from 0.3 to 5.6 nM. It is selective for CB
2 over CB
1 receptors, where it has K
i values ranging from 305 to >10,000 nM. SR 144528 blocks the inhibitory effects of CP 55,940 on forskolin-induced adenylyl cyclase activity in CHO cells expressing hCB
2 (IC
50 = 10 nM) but not in cells expressing hCB
1 (IC
50 = >10 μM). SR 144528 has been used to investigate the contribution of the CB
2 receptor in the control of pain initiation as well as suppression of inflammation and immune activation.
Uses
SR 144528 acts as a selective peripheral cannabinoid (CB2) receptor inverse agonist. Used in studies involving application of cannabis and anticancer drugs and multi-drug resistance (MDR) of the patient.
Uses
SR144528 has been used as a cannabinoid CB2 receptor antagonist:
- to study its blocking effect on the anti-dyskinetic functionality of HU-308
- to study its effects on spontaneous excitatory postsynaptic currents (sEPSCs) from the globus pallidus neurons
- to analyze its effect on the gastric emptying in rats
Definition
ChEBI: SR 144528 is a secondary carboxamide resulting from the formal condensation of the carboxy group of 5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)-1H-pyrazole-3-carboxylic acid with the amino group of (1S,2S,4R)-1,3,3-trimethylbicyclo[2.2.1]heptan-2-amine. A potent and selective cannabinoid receptor type 2 (CB2 receptor) inverse agonist (Ki = 0.6 nM). It has a role as a CB2 receptor antagonist and an EC 2.3.1.26 (sterol O-acyltransferase) inhibitor. It is a member of pyrazoles, a secondary carboxamide, a member of monochlorobenzenes and a bridged compound.
Biochem/physiol Actions
SR144528 is a potent and highly selective cannabinoid CB2 receptor inverse agonist. SR144528 exhibited a Ki of 0.6 nM at CB2 compared to 400 nM at the related CB1 receptor.
in vitro
sr 144528 displayed subnanomolar affinity for both the rat spleen and cloned human cb2 receptors and had a 700-fold lower affinity for both the rat brain and cloned human cb1 receptors. moreover, sr 144528 showed no affinity for more than 70 receptors, ion channels or enzymes tested. sr 144528 could antagonize the inhibitory effects of the cannabinoid receptor agonist cp 55,940 on forskolin-stimulated adenylyl cyclase activity in cell lines expressing the human cb2 receptor but not in cells expressing the human cb1. in addition, sr 144528 could selectively block the mitogen-activated protein kinase activity that was induced by cp 55,940 in cell lines expressing human cb2 while an ic50 value of more than 1 μm was observed in cells expressing human cb1 [1].
in vivo
animal study showed that oral administration of sr 144528 could totally displace the ex vivo [3h]-cp 55,940 binding to mouse spleen membranes with a long action duration. whereas, after the oral route sr 144528 did not interact with the cannabinoid receptor expressed in the mouse brain cb1 [1].
References
1) Rinaldi-Carmona et al. (1998), SR-144528, the first potent and selective antagonist of the CB2 cannabinoid receptor; J. Pharmacol. Exp. Ther., 284 644
2) Portier et al. (1999), SR-144528, an antagonist for the peripheral cannabinoid receptor that behaves as an inverse agonist; J. Pharmacol. Exp. Ther., 288 582
