Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB 1 receptor ligand antagonists

Murineddu, Gabriele; Deligia, Francesco; Ragusa, Giulio; García-Toscano, Laura; Gómez‐Cañas, María; Asproni, Battistina; Satta, Valentina; Cichero, Elena; Pazos, Ruth; Fossa, Paola; Loriga, Giovanni; Fernández‐Ruiz, Javier; Pinna, Gérard Aimè

doi:10.1016/j.bmc.2017.11.051

Cited by 10 publications

(7 citation statements)

References 25 publications

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“…Innovative therapeutic interventions to alleviate these metabolic disorders are in urgent demand. Since, the discovery of the cannabinoid receptor 1 (CB1R) system, and the subsequent disclosure of its critical roles in the developing and progression of obesity, the pursuit for effective CB1R antagonists to manage morbid obesity haven’t lost its momentum ( Sharma et al, 2014 ; Murineddu et al, 2017 ). After the well-known first in-class selective CB1R antagonist/inverse agonist SR141716 (rimonabant) approved by the European Medicines Agency (EMA) and then withdrawn from market in 2008, the second generation of CB1R antagonists are becoming the strategy in progress to solve the problems derived from the first generation of CB1R antagonists such as SR141716 ( Wu et al, 2011 ; Chorvat, 2013 ).…”

Section: Introductionmentioning

confidence: 99%

Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice

Guina²,

Mou

et al. 2018

Front. Pharmacol.

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Effect of peripheral cannabinoid receptor 1 (CB1R) blockade by AM6545 in the monosodium glutamate (MSG)-induced hypometabolic and hypothalamic obesity was observed, and the impact on intraperitoneal adipose tissue and adipokines was investigated. The MSG mice is characterized by excessive abdominal obesity, and combined with dyslipidemia and insulin resistance. 3-Week AM6545 treatment dose-dependently decreased the body weight, intraperitoneal fat mass, and rectified the accompanied dyslipidemia include elevated serum triglyceride, total cholesterol, free fatty acids, and lowered LDLc level. Glucose intolerance and hyperinsulinemia were also alleviated. But AM6545 didn’t affect the food-intake consistently through the experiment. In line with the reduction on fat mass, the size of adipocyte was reduced markedly. Most interestingly, AM6545 showed significant improvement on levels of circulating adipokines including lowering leptin, asprosin and TNFα, and increasing HMW adiponectin. Correspondingly, dysregulated gene expression of lipogenesis, lipolysis, and adipokines in the adipose tissue were nearly recovered to normal level after AM6545 treatment. Additionally, western blot analysis revealed that AM6545 corrected the elevated CB1R and PPARγ protein expression, while increased the key energy uncoupling protein UCP1 expression in adipose tissue. Taken together, the current study indicates that AM6545 induced a comprehensive metabolic improvement in the MSG mice including counteracting the hypometabolic and hypothalamic obesity, and improving the accompanied dyslipidemia and insulin resistance. One key underlying mechanism is related to ameliorate on the metabolic deregulation of adipose tissue, the synthesis and secretion of adipokines were thus rectified, and finally the catabolism was increased and the anabolism was reduced in intraperitoneal adipose tissue. Findings from this study will provide the valuable information about peripheral CB1R antagonist in managing hypometabolic obesity.

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Section: Introductionmentioning

confidence: 99%

Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice

Guina²,

Mou

et al. 2018

Front. Pharmacol.

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“…In rCB1 structure (PDB ID: 5U09), the complexed antagonist molecule was taranabant, and the main interactions that occur between these molecules and rCB1, favorable to antagonism, are related to the following amino acids: Phe102, Met103, Asp104, Ile105, Phe108, Ile119, Ser123, Ile169, Phe170, Phe174, Leu193, Val196, Phe268, Trp279, Trp356, Leu359, Met363, Phe379, Ala380, Met384, Cys386 e Leu387 [52].…”

Section: Molecular Docking Analysismentioning

confidence: 99%

“…Murineddu and collaborators [52], when docking antagonist AM6538 into the rCB1 structure (PDB ID: The rCB1 orthosteric pocket shows hydrophobic characteristics since this receptor is activated by lipids [30], which explains the fact that the vast majority of occurring interactions are hydrophobic. All phytocannabinoids interacted with the N-terminal domain (mostly hydrophobic bonds), which is related to the restriction of membrane access by ligands from the extracellular side [51].…”

Section: Molecular Docking Analysismentioning

confidence: 99%

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Pharmacophore-based Virtual Screening From Phytocannabinoids for Anti-obesity Activity

Correia

Ferreira

Lima

et al. 2021

Preprint

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Search for new pharmacological alternatives for obesity is based on the design and development of compounds that can aid in weight loss so that they can be used safely and effectively over a long period while maintaining their function. The endocannabinoid system is related to obesity by increasing orexigenic signals and reducing satiety signals. Cannabis sativa is a medicinal plant of polypharmaceutical potential that has been widely studied for various medicinal purposes. The in silico evaluation of their natural cannabinoids (also called phytocannabinoids) for anti-obesity purpose stems from the existence of synthetic cannabinoid compounds that have already presented this result, but which did not guarantee patient safety. In order to find new molecules from C. sativa phytocannabinoids, with the potential to interact with the pharmacological target cannabinoid receptor 1, a pharmacophore-based virtual screening was performed, including the evaluation of physicochemical, pharmacokinetic, toxicological predictions and molecular docking. The results obtained from the ZINC12 database pointed to Zinc 69 (ZINC33053402) and Zinc 70 (ZINC19084698) molecules as promising anti-obesity agents. Molecular Dynamics (MD) studies discloses that both complexes were stable by analyzing the RMSD (Root Mean Square Deviation) values, and the binding free energy values demonstrate that the selected structures can interact and inhibit their catalytic activity.

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“…Most of the pyridazinone derivatives are derived from substitution of the pyridazinone oxygen, nitrogen and C4/C5/C6 carbon positions. Pyridazinone can be used for the synthesis of a large variety of heterocyclic compounds and as intermediate for a broad spectrum of drug synthesis (Abdelbaset et al, 2018;Ahmad et al, 2018;Barberot et al, 2018;Boukharsa et al, 2018;Çetin and Bildirici, 2018;Ewida et al, 2018;Ibrar et al, 2018;Murineddu et al, 2018;Wang et al, 2018).…”

Section: Selectivementioning

confidence: 99%

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

Int¹

2019

Preprint

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A series of heterocyclic compounds incorporating pyridazine moiety were for diverse biological activities. Pyridazines and pyridazinones derivatives showed wide spectrum of biological activities such as vasodialator, cardiotonic, anticonvulsant, antihypertensive, antimicrobial, anti-inflammatory, analgesic, anti-feedant, herbicidal, and various other biological, agrochemical and industrial chemical activities. The results illustrated that the synthesized pyridazine/pyridazine compounds have diverse and significant biological activities. Mechanistic insights into the biological properties of pyridazinone derivatives and various synthetic techniques used for their synthesis are also described.

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Novel sulfenamides and sulfonamides based on pyridazinone and pyridazine scaffolds as CB 1 receptor ligand antagonists

Cited by 10 publications

References 25 publications

Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice

Peripheral CB1 Receptor Neutral Antagonist, AM6545, Ameliorates Hypometabolic Obesity and Improves Adipokine Secretion in Monosodium Glutamate Induced Obese Mice

Pharmacophore-based Virtual Screening From Phytocannabinoids for Anti-obesity Activity

Diverse chemical and biological potentials of various pyridazine and pyridazinone derivatives

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