Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain

Rinaldi‐Carmona, Murielle; Pialot, Françoise; Congy, Christian; Redon, Elsa; Barth, Francis; Bachy, A; Brelière, Jean-Claude; Soubrié, Philippe; Fur, G. Le

doi:10.1016/0024-3205(96)00085-9

Cited by 121 publications

(77 citation statements)

References 11 publications

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“…For example, anandamide and methanandamide have 2 -10 fold lower affinity than rimonabant to displace the agonist ligand [ 3 H]CP 55940 (Abadji et al, 1994, Adams et al, 1995, Adams et al, 1998. In addition, anandamide has 100 fold lower affinity than rimonabant to displace [ 3 H]rimonabant itself (Rinaldi-Carmona et al, 1996). Although these two agonists have clearly lower in vitro receptor affinity than rimonabant, the question we have addressed is the in vivo occupancy associated with pharmacological effects.…”

Section: Displacement Of An Inverse Agonist Radioligand By Agonists Lmentioning

confidence: 99%

“…The special property of inverse agonists is their ability, in at least some systems, to reduce the output signal below baseline levels found in the absence of agonist. Rinaldi-Carmona et al (1996) studied the binding of [ 3 H]rimonabant, an inverse agonist. They found that some agonists, like CP 55,940 and WIN 55,212-2, had competitive inhibition but that the endogenous cannabinoid, anandamide, had noncompetitive / allosteric effects.…”

Section: Displacement Of An Inverse Agonist Radioligand By Agonists Lmentioning

confidence: 99%

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Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

et al. 2008

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Abstract[ 11 C]MePPEP is an inverse agonist and a radioligand developed to image cannabinoid CB 1 receptors with positron emission tomography (PET). It provides reversible, high specific signal in monkey brain. We assessed [ 11 C]MePPEP in rodent brain with regard to receptor selectivity, susceptibility to transport by P-glycoprotein (P-gp), sensitivity to displacement by agonists, and accumulation of radiometabolites. We used CB 1 receptor knockout mice and P-gp knockout mice to assess receptor selectivity and sensitivity to efflux transport, respectively. Using serial measurements of PET brain activity and plasma concentrations of [ 11 C]MePPEP, we estimated CB 1 receptor density in rat brain as distribution volume. CB 1 knockout mice showed only nonspecific brain uptake, and [ 11 C]MePPEP was not a substrate for P-gp. Direct acting agonists anandamide (10 mg/kg), methanandamide (10 mg/kg), CP 55,940 (1 mg/kg), and indirect agonist URB597 (0.3 and 0.6 mg/kg) failed to displace [ 11 C]MePPEP, while the inverse agonist rimonabant (3 and 10 mg/kg) displaced >65% of [ 11 C] MePPEP. Radiometabolites represented ∼13% of total radioactivity in brain between 30 and 120 min. [ 11 C]MePPEP was selective for the CB 1 receptor, was not a substrate for P-gp, and was more potently displaced by inverse agonists than agonists. The low potency of agonists suggests either a large receptor reserve or non-overlapping binding sites for agonists and inverse agonists. Radiometabolites of [ 11 C]MePPEP in brain caused distribution volume to be overestimated by ∼13%.

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Section: Displacement Of An Inverse Agonist Radioligand By Agonists Lmentioning

confidence: 99%

Section: Displacement Of An Inverse Agonist Radioligand By Agonists Lmentioning

confidence: 99%

Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

et al. 2008

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“…In vitro autoradiographic studies with radiolabeled high-affinity ligands (Herkenham et al, 1990;Jansen et al, 1992;Thomas et al, 1992;Rinaldi-Carmona et al, 1996;Glass et al, 1997) have demonstrated high concentrations of CB 1 cannabinoid receptors in several regions of the rat and human brain, including the substantia nigra and its output regions, including the basal ganglia. High concentrations are also found in globus pallidus, hippocampus, and cerebellum.…”

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confidence: 99%

Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo

Gatley

Lan²,

Volkow

et al. 1998

Journal of Neurochemistry

116

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Abstract:The major active ingredient of marijuana, (-)-z~9 -tetrahydrocannabinol, exerts its psychoactive effects via binding to cannabinoid CB1 receptors, which are widely distributed in the brain. Radionuclide imaging of CB1 receptors in living human subjects would help explore the presently unknown physiological roles of this receptor system, as well as the neurochemical consequences of marijuana dependence. Currently available cannabinoid receptor radioligands are exceedingly lipophilic and unsuitable for in vivo use. We report the development of a novel radioligand,

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“…All of these actions appear to be exerted through one or more members of the PTX-sensitive G i family of GTP-binding regulatory proteins that comprises G i , G o . While synthetic (CP-55, 940, WIN55212-2) cannabinoid ligands cannot discriminate between CB 1 and CB 2 receptors, selective antagonists have recently been developed that specifically target either CB 1 (SR141716) (13,14) or CB 2 receptors (SR 144528) (15). Several studies revealed that receptor activation can occur spontaneously in the absence of an agonist.…”

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confidence: 99%

Regulation of Peripheral Cannabinoid Receptor CB2Phosphorylation by the Inverse Agonist SR 144528

Bouaboula

Dussossoy

Casellas

1999

Journal of Biological Chemistry

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We recently demonstrated that the selective cannabinoid receptor antagonist SR 144528 acts as an inverse agonist that blocks constitutive mitogen-activated protein kinase activity coupled to the spontaneous autoactivated peripheral cannabinoid receptor (CB 2 ) in the Chinese hamster ovary cell line stably transfected with human CB 2 . In the present report, we studied the effect of SR 144528 on CB 2 phosphorylation. The CB 2 phosphorylation status was monitored by immunodetection using an antibody specific to the COOH-terminal CB 2 which can discriminate between phosphorylated and non-phosphorylated CB 2 isoforms at serine 352. We first showed that CB 2 is constitutively active, phosphorylated, and internalized at the basal level. By blocking autoactivated receptors, inverse agonist SR 144528 treatment completely inhibited this phosphorylation state, leading to an up-regulated CB 2 receptor level at the cell surface, and enhanced cannabinoid agonist sensitivity for mitogen-activated protein kinase activation of Chinese hamster ovary-CB 2 cells. After acute agonist treatment, serine 352 was extensively phosphorylated and maintained in this phosphorylated state for more than 8 h after agonist treatment. The cellular responses to CP-55,940 were concomitantly abolished. Surprisingly, CP-55,940-induced CB 2 phosphorylation was reversed by SR 144528, paradoxically leading to a nonphosphorylated CB 2 which could then be fully activated by CP-55,940. The process of CP-55,940-induced receptor phosphorylation followed by SR 144528-induced receptor dephosphorylation kept recurring many times on the same cells, indicating that the agonist switches the system off but the inverse agonist switches the system back on. Finally, we showed that autophosphorylation and CP-55,940-induced serine 352 CB 2 phosphorylation involve an acidotropic GRK kinase, which does not use G i ␤␥. In contrast, SR 144528-induced CB 2 dephosphorylation was found to involve an okadaic acid and calyculin A-sensitive type 2A phosphatase. Several studies revealed that receptor activation can occur spontaneously in the absence of an agonist. This discovery led to a reclassification of antagonists as neutral antagonists or inverse agonists. Neutral antagonists block agonist action without any effect on constitutive activity (16 -19), whereas agonists block agonist action but also suppress constitutive activity.We recently demonstrated the agonist-independent activity of CB 1 and CB 2 receptors expressed in mammalian cells following transfection (20,21). We also showed that the CB 1 antagonist SR141716 and the CB 2 antagonist SR 144528 not only block the actions of cannabinoid agonists but they also suppress the constitutive activity of these receptors, indicating that these molecules act as inverse agonists. Furthermore, we revealed for the first time a novel property of these inverse agonists. We demonstrated that they also switch off the activation induced by other unrelated G i -dependent receptors such as insulin or insulin-like growth factor-1 receptors...

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Characterization and distribution of binding sites for [3H]-SR 141716A, a selective brain (CB1) cannabinoid receptor antagonist, in rodent brain

Cited by 121 publications

References 11 publications

Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

Positron emission tomography imaging using an inverse agonist radioligand to assess cannabinoid CB1 receptors in rodents

Imaging the Brain Marijuana Receptor: Development of a Radioligand that Binds to Cannabinoid CB1 Receptors In Vivo

Regulation of Peripheral Cannabinoid Receptor CB2Phosphorylation by the Inverse Agonist SR 144528

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