Prospective therapeutic agents for obesity: Molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists

Sharma, Mayank Kumar; Murumkar, Prashant R.; Kanhed, Ashish M.; Giridhar, Rajani; Yadav, Mange Ram

doi:10.1016/j.ejmech.2014.04.011

Cited by 61 publications

(38 citation statements)

References 209 publications

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“…In this regard, reinstating FAAH activity to consequently suppress AEA levels may be sufficient to reverse an obese state and thus supports the putative efficacy of antiobesity therapies targeting the eCB system. Indeed, CB1 receptor antagonists have proven effective at combatting obesity, but their utility was compromised by the fact that they also cause significant psychiatric side effects (58).…”

Section: Discussionmentioning

confidence: 99%

Role for fatty acid amide hydrolase (FAAH) in the leptin-mediated effects on feeding and energy balance

Balsevich

Sticht

Bowles

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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Endocannabinoid signaling regulates feeding and metabolic processes and has been linked to obesity development. Several hormonal signals, such as glucocorticoids and ghrelin, regulate feeding and metabolism by engaging the endocannabinoid system. Similarly, studies have suggested that leptin interacts with the endocannabinoid system, yet the mechanism and functional relevance of this interaction remain elusive. Therefore, we explored the interaction between leptin and endocannabinoid signaling with a focus on fatty acid amide hydrolase (FAAH), the primary degradative enzyme for the endocannabinoid -arachidonoylethanolamine (anandamide; AEA). Mice deficient in leptin exhibited elevated hypothalamic AEA levels and reductions in FAAH activity while leptin administration to WT mice reduced AEA content and increased FAAH activity. Following high fat diet exposure, mice developed resistance to the effects of leptin administration on hypothalamic AEA content and FAAH activity. At a functional level, pharmacological inhibition of FAAH was sufficient to prevent leptin-mediated effects on body weight and food intake. Using a novel knock-in mouse model recapitulating a common human polymorphism (FAAH C385A; rs324420), which reduces FAAH activity, we investigated whether human genetic variance in affects leptin sensitivity. While WT (CC) mice were sensitive to leptin-induced reductions in food intake and body weight gain, low-expressing FAAH (AA) mice were unresponsive. These data demonstrate that FAAH activity is required for leptin's hypophagic effects and, at a translational level, suggest that a genetic variant in the FAAH gene contributes to differences in leptin sensitivity in human populations.

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Section: Discussionmentioning

confidence: 99%

Role for fatty acid amide hydrolase (FAAH) in the leptin-mediated effects on feeding and energy balance

Balsevich

Sticht

Bowles

et al. 2018

Proc. Natl. Acad. Sci. U.S.A.

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“…In clinical terms, a surrogate decision-maker for body fat content is the body mass index (BMI), which exceeds 30 kg/m 2 called obesity [1][2][3][4].…”

Section: Introductionmentioning

confidence: 99%

Hypolipidemic effect of dihydroisoquinoline oxaziridine in high-fat diet-fed rats

Aydi

Gara

Chaaben

et al. 2016

Biomedicine & Pharmacotherapy

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“…Therefore, CB1R has been regarded as an attractive therapeutic target for obesity for the past two decades (Di Marzo et al, 2011; Gatta-Cherifi and Cota, 2015; Kaur et al, 2016; Lu et al, 2016). The first-in-class selective CB1R antagonist and inverse agonist rimonabant (Acomplia; SR141716A), which was successfully approved and introduced into the European market in June of 2006, was anticipated to provide an effective treatment for obesity (Di Marzo, 2008; Sharma et al, 2014). Unfortunately, undesirable neuropsychiatric adverse effects, including anxiety, depression, and suicide were observed in some patients, and these central nervous system effects led to the withdrawal of SR141716A from the market in October of 2008 (Janero and Makriyannis, 2009; Le Foll et al, 2009).…”

Section: Introductionmentioning

confidence: 99%

Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice

Chen¹,

Shui²,

Liu

et al. 2017

Front. Pharmacol.

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The clinical development of the first generation of globally active cannabinoid 1 receptor (CB1R) antagonists was suspended because of their adverse neuropsychiatric effects. Selective blockade of peripheral CB1Rs has the potential to provide a viable strategy for the treatment of severe obesity while avoiding these central nervous system side effects. In the current study, a novel compound (TXX-522) was rationally designed based on the parent nucleus of a classical CB1R-selective antagonist/inverse agonist, rimonabant (SR141716A). Docking assays indicate that TXX-522 was bound with the CB1R in a mode similar to that of SR141716A. TXX-522 showed good binding, CB1R-selectivity (over the CB2R), and functional antagonist activities in a range of in vitro molecular and cellular assays. In vivo analysis of the steady state distribution of TXX-522 in the rat brain and blood tissues and the assay of its functional effects on CB1R activity collectively showed that TXX-522 showed minimal brain penetration. Moreover, the in vivo pharmacodynamic study further revealed that TXX-522 had good oral bioavailability and a potent anti-obesity effect, and ameliorated insulin resistance in high-fat diet-induced obese mice. No impact on food intake was observed in this model, confirming the limited brain penetration of this compound. Thus, the current study indicates that TXX-522 is a novel and potent peripherally acting selective CB1R antagonist with the potential to control obesity and related metabolic disorders.

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Prospective therapeutic agents for obesity: Molecular modification approaches of centrally and peripherally acting selective cannabinoid 1 receptor antagonists

Cited by 61 publications

References 209 publications

Role for fatty acid amide hydrolase (FAAH) in the leptin-mediated effects on feeding and energy balance

Role for fatty acid amide hydrolase (FAAH) in the leptin-mediated effects on feeding and energy balance

Hypolipidemic effect of dihydroisoquinoline oxaziridine in high-fat diet-fed rats

Novel Peripherally Restricted Cannabinoid 1 Receptor Selective Antagonist TXX-522 with Prominent Weight-Loss Efficacy in Diet Induced Obese Mice

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