Design and synthesis of the CB1 selective cannabinoid antagonist AM281: A potential human SPECT ligand

Lan, Ruoxi; Lü, Qian; Fan, Pusheng; Gatley, John; Volkow, Nora D.; Fernando, Susanthi R.; Pertwee, Roger G.; Makriyannis, Alexandros

doi:10.1208/ps010204

Cited by 77 publications

(49 citation statements)

References 23 publications

(27 reference statements)

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“…AM6545 binding to CB1R was assessed in competition displacement assays using [ 3 H]CP-55,940 as the radioligand and crude membranes from mouse brain for CB1R or HEK293 cells stably transfected with the mouse CB2R, as described previously (58). KI values were determined from 3 independent experiments performed in triplicate.…”

Section: Synthetic Procedures and Compound Characterization 5-(4-[4-mentioning

confidence: 99%

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Tam¹,

Vemuri²,

Liu³

et al. 2010

J. Clin. Invest.

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152

272

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Obesity and its metabolic consequences are a major public health concern worldwide. Obesity is associated with overactivity of the endocannabinoid system, which is involved in the regulation of appetite, lipogenesis, and insulin resistance. Cannabinoid-1 receptor (CB 1 R) antagonists reduce body weight and improve cardiometabolic abnormalities in experimental and human obesity, but their therapeutic potential is limited by neuropsychiatric side effects. Here we have demonstrated that a CB 1 R neutral antagonist largely restricted to the periphery does not affect behavioral responses mediated by CB 1 R in the brains of mice with genetic or diet-induced obesity, but it does cause weight-independent improvements in glucose homeostasis, fatty liver, and plasma lipid profile. These effects were due to blockade of CB 1 R in peripheral tissues, including the liver, as verified through the use of CB 1 R-deficient mice with or without transgenic expression of CB 1 R in the liver. These results suggest that targeting peripheral CB 1 R has therapeutic potential for alleviating cardiometabolic risk in obese patients. IntroductionEndocannabinoids are endogenous lipid mediators that interact with the same G protein-coupled receptors - CB 1 R and CB 2 R - that recognize plant-derived cannabinoids, and they regulate a broad range of physiological functions. CB 1 Rs are expressed at very high levels in the brain but are also present at much lower yet functionally relevant concentrations in various peripheral tissues, whereas the expression of CB 2 Rs is largely limited to cells of the immune and hematopoietic systems. Activation of CB 1 R results in increased appetite, insulin resistance, and increased hepatic lipogenesis, which suggests the involvement of the endocannabinoid/ CB 1 R system in obesity and its metabolic consequences (1). Indeed, obesity and its metabolic complications are characterized by an overactive endocannabinoid system (2-5), and chronic treatment with CB 1 R antagonists leads to weight loss and improved cardiometabolic risk profile in obese rodents (6, 7) and humans (8-11). However, concern over neuropsychiatric side effects, including anxiety, depression, and suicidal ideation (12), prevented approval of the first-in-class CB 1 R antagonist rimonabant in the United States and led to its withdrawal from the European market as well as the withdrawal of related compounds from preclinical development (13). Although the exact role of the endocannabinoid system in the control of mood and anxiety-like behaviors is not clear, CB 1 R in the prefrontal cortex, amygdala, and the mesolimbic dopaminergic reward pathway have been linked to the control of these behaviors (14). On the other hand, CB 1 Rs are also present in peripheral tissues including the liver (15-17), skeletal muscle (18,19), endocrine

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Section: Synthetic Procedures and Compound Characterization 5-(4-[4-mentioning

confidence: 99%

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Tam¹,

Vemuri²,

Liu³

et al. 2010

J. Clin. Invest.

Self Cite

152

272

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“…2 b). In addition, we examined the effect of a potent CB1R-selective antagonist, AM281 [24] . AM281 (0.5 mg/kg i.p.)…”

Section: Resultsmentioning

confidence: 99%

Endocannabinergic Modulation of Interleukin-1β in Mouse Hippocampus under Basal Conditions and after in vivo Systemic Lipopolysaccharide Stimulation

Csölle

Sperlágh

2011

Neuroimmunomodulation

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Objective: Cannabinoids play an important role in the suppression of proinflammatory cytokine production in the periphery and brain. In this study, we explored whether endogenous activation of cannabinoid (CB) 1 receptors (CB1Rs) affects interleukin (IL)-1β levels in the mouse hippocampus under basal conditions and following stimulation with in vivo bacterial lipopolysaccharide (LPS, 250 µg/kg i.p.). Methods: IL-1β levels were determined in the hippocampi of wild-type (WT), CB1R–/– and P2X₇ receptor (P2X₇R)–/– mice using an ELISA kit. Results: Basal but not LPS-induced IL-1β levels were downregulated when CB1R function was abrogated by genetic deletion, suggesting that endocannabinoids contributed to basal IL-1β content in the mouse hippocampus. AM251 (3 mg/kg i.p.), an antagonist of CB1Rs, also inhibited basal IL-1β protein in WT but not in CB1R–/– mice. In the absence of P2X₇R, LPS-induced IL-1β production was lower, while the inhibitory effect of CB1R antagonists on basal IL-1β was significantly attenuated. The LPS-induced elevation in IL-1β production was decreased in the presence of AM251 and AM281, with no significant difference between WT and P2X₇R–/– mice. Conclusions: CB1Rs are responsible for the modulation of basal IL-1β levels in the hippocampus, while the effects of CB1 antagonists on systemic LPS-induced IL-1β concentrations are independent of CB1Rs.

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“…There are numerous reports that, like SR141716A, AM251 and AM281 can attenuate in vivo or in vitro responses to established cannabinoid receptor agonists (e.g. Cosenza et al 2000;Gifford et al 1997;Hájos and Freund 2002a;Lan et al 1999a;Simoneau et al 2001).…”

Section: Selective Cb 1 Receptor Antagonistsmentioning

confidence: 99%

Pharmacological Actions of Cannabinoids

Pertwee

Handbook of Experimental Pharmacology

502

515

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Design and synthesis of the CB1 selective cannabinoid antagonist AM281: A potential human SPECT ligand

Cited by 77 publications

References 23 publications

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Peripheral CB1 cannabinoid receptor blockade improves cardiometabolic risk in mouse models of obesity

Endocannabinergic Modulation of Interleukin-1β in Mouse Hippocampus under Basal Conditions and after in vivo Systemic Lipopolysaccharide Stimulation

Pharmacological Actions of Cannabinoids

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