Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole – LH 21

Pavón-Morón, Francisco Javier; Bilbao, Ainhoa; Hernandez-Folgado, Laura; Cippitelli, Andrea; Jagerovic, Nadine; Abellán, Gumersindo; Rodríguez‐Franco, María Isabel; Serrano, Antonia; Macías, Manuel; Gómez, R.; Navarro, Miguel; Goya, Pilar; Fonseca, Fernando Rodrı́guez de

doi:10.1016/j.neuropharm.2006.03.029

Cited by 111 publications

(112 citation statements)

References 43 publications

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“…The acute effects of NP-1 on feeding behavior and other biochemical determinations were analyzed after stabilization of weight curves in both diet groups. For feeding studies, animals were food deprived for 24 h, with access to water ad libitum as described (22). Fifteen minutes before the test, NP-1 (5 or 50 mg/kg) or vehicle was administered ip, and animals were returned to their home cage.…”

Section: Methodsmentioning

confidence: 99%

Adiponectin promoter activator NP-1 reduces body weight and hepatic steatosis in high-fat diet-fed animals

Serrano

Pavón-Morón

Suárez

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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Enhancement of adiponectin level has been shown to have beneficial effects, including antiobesity, antidiabetic, and hepatoprotective effects. This evidence supports the therapeutic utility of adiponectin in complicated obesity. The present study characterized the in vivo effects of sustained adiponectin release by NP-1, a new class of thiazol derivative that increases adiponectin levels. Acute administration of NP-1 reduced feeding, increased plasma adiponectin, and improved insulin sensitivity without inducing malaise, as revealed by conditioned taste aversion studies. Short-term (7 days) treatment with NP-1 also reduced feeding and body weight gain and increased phosphorylation of AMPK in muscle, a main intracellular effector of adiponectin. NP-1 was also evaluated in diet-induced obesity, and adult male Wistar rats were fed two different types of diet: a standard high-carbohydrate/low-fat diet (SD) and a high-fat diet (HFD). Once obesity was established, animals were treated daily with NP-1 (5 mg/kg) for 14 consecutive days. Chronic NP-1 induced body weight loss and reduction of food intake and resulted in both a marked decrease in liver steatosis and an improvement of biochemical indexes of liver damage in HFD-fed rats. However, a marked induction of tolerance in adiponectin gene transcription and release was observed after chronic NP-1 with respect to the acute actions of this drug. The present results support the role of adiponectin signaling in diet-induced obesity and set in place a potential use of compounds able to induce adiponectin release for the treatment of obesity and nonalcoholic fatty liver, with the limits imposed by the induction of pharmacological tolerance.

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Section: Methodsmentioning

confidence: 99%

Adiponectin promoter activator NP-1 reduces body weight and hepatic steatosis in high-fat diet-fed animals

Serrano

Pavón-Morón

Suárez

et al. 2012

American Journal of Physiology-Endocrinology and Metabolism

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“…A nonbrain-penetrating compound clearly represents an extremely valuable tool in addressing whether inhibiting peripheral CB1R can lead to metabolic efficacy. Toward that end, Pavon 44 hypothesized that a newly discovered molecule, LH-21, might not cross the blood-brain barrier. However, LH-21 has since been shown to be brain penetrant and its weight loss efficacy is not mediated by CB1R, because LH-21 is still effective in CB1R KO mice.…”

Section: Peripheral Physiological Effects Vs Peripheral Site Of Actiomentioning

confidence: 99%

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

Fong

Heymsfield

2009

Int J Obes

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Rimonabant and taranabant are two extensively studied cannabinoid-1 receptor (CB1R) inverse agonists. Their effects on in vivo peripheral tissue metabolism are generally well replicated. The central nervous system site of action of taranabant or rimonabant is firmly established based on brain receptor occupancy studies. At the whole-body level, the mechanism of action of CB1R inverse agonists includes a reduction in food intake and an increase in energy expenditure. At the tissue level, fat mass reduction, liver lipid reduction and improved insulin sensitivity have been shown. These effects on tissue metabolism are readily explained by CB1R inverse agonist acting on brain CB1R and indirectly influencing the tissue metabolism through the autonomic nervous system. It has also been hypothesized that rimonabant acts directly on adipocytes, hepatocytes, pancreatic islets or skeletal muscle in addition to acting on brain CB1R, although strong support for the contribution of peripherally located CB1R to in vivo efficacy is still lacking. This review will carefully examine the published literature and provide a perspective on what new tools and studies are required to address the peripheral site of action hypothesis.

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“…Some of these compounds have been identified as being actively pursued in the biopharmaceutical industry as leads for the pharmacotherapy of obesity and related metabolic disorders, including type 2 diabetes (table 1) [16]. In general, such lead selective CB1 receptor antagonists for weight-management have 8 demonstrated acute preclinical activity in reducing food intake and body weight, and longer-term efficacy with chronic feeding in non-obese rodents and standard dietary and genetic obesity models [70][71][72][73][74][75][76][77]. Measurements of energy expenditure, adipose tissue mass and distribution and metabolic parameters (e.g., plasma glucose and insulin levels, lipids) have also been routine components of the lead evaluation process.…”

Section: The Cb1 Receptor Antagonistsmentioning

confidence: 99%

The Endocannabinoid System: A Promising Target for the Management of Type 2 Diabetes

Scheen

2009

CPPS

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Conflict of interest :AJ Scheen is a consultant for sanofi-aventis, AstraZeneca, GlaxoSmithKline, and has received lecture fees from sanofi-aventis. 1 SUMMARY (Max 250 words : 250)Type 2 diabetes is closely related to abdominal obesity and is generally associated with other cardiometabolic risk factors, resulting in a high incidence of cardiovascular complications.Several animal and human observations suggest that the endocannabinoid (EC) system is overactivated in presence of abdominal obesity and/or diabetes, and contributes to disturbances of energy balance and metabolism. Not only it regulates the intake of nutrients through central mechanisms located within the hypothalamus and limbic area, but it also intervenes in transport, metabolism and deposit of the nutrients in the digestive tract, liver, adipose tissue, skeletal muscle, and possibly pancreas. Activation of both central and peripheral CB1 receptors promotes weight gain and associated metabolic changes. Conversely, rimonabant, the first selective CB 1 receptor antagonist in clinical use, has been shown to reduce body weight, waist circumference, triglycerides, blood pressure, insulin resistance and C-reactive protein levels, and to increase HDL cholesterol and adiponectin concentrations in both non-diabetic and diabetic overweight/obese patients. In addition, a 0.5-0.7% reduction in glycated hemoglobin (HbA1c) levels was observed in metformin-or sulfonylurea-treated patients with type 2 diabetes and in drug-naïve diabetic patients. Almost half of metabolic changes occurred beyond weight loss, in agreement with direct peripheral effects. Rimonabant was generally well-tolerated, but with a slightly higher incidence of depressed mood disorders, anxiety, nausea and dizziness compared to placebo. New trials are supposed to confirm the potential role of rimonabant (and other CB1 neutral antagonists or inverse agonists) in overweight/obese patients with type 2 diabetes and high risk cardiovascular disease.

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Antiobesity effects of the novel in vivo neutral cannabinoid receptor antagonist 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-3-hexyl-1H-1,2,4-triazole – LH 21

Cited by 111 publications

References 43 publications

Adiponectin promoter activator NP-1 reduces body weight and hepatic steatosis in high-fat diet-fed animals

Adiponectin promoter activator NP-1 reduces body weight and hepatic steatosis in high-fat diet-fed animals

Cannabinoid-1 receptor inverse agonists: current understanding of mechanism of action and unanswered questions

The Endocannabinoid System: A Promising Target for the Management of Type 2 Diabetes

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