scholarly journals Functional Selectivity of a Biased Cannabinoid-1 Receptor (CB1R) Antagonist

2021 ◽  
Author(s):  
Ziyi Liu ◽  
Malliga R. Iyer ◽  
Grzegorz Godlewski ◽  
Tony Jourdan ◽  
Jie Liu ◽  
...  
Keyword(s):  
Functional Selectivity ◽  
Cannabinoid 1 Receptor

Lack of Regulatory Changes of µ-Opioid Receptors by 14-Methoxymetopon Treatment in Rat Brain. Further Evidence for Functional Selectivity

2014 ◽  
Vol 19 (42) ◽  
pp. 7348-7354 ◽  
Author(s):  
Resat Cinar ◽  
Orsolya Kekesi ◽  
Erika Birkas ◽  
Gabriella Fabian ◽  
Helmut Schmidhammer ◽  
...  
Keyword(s):  
Rat Brain ◽  
Opioid Receptors ◽  
Functional Selectivity ◽  
Regulatory Changes

scholarly journals Renal Proximal Tubule Cell Cannabinoid-1 Receptor Regulates Bone Remodeling and Mass via a Kidney-to-Bone Axis

Cells ◽  
2021 ◽  
Vol 10 (2) ◽  
pp. 414
Author(s):  
Saja Baraghithy ◽  
Yael Soae ◽  
Dekel Assaf ◽  
Liad Hinden ◽  
Shiran Udi ◽  
...  
Keyword(s):  
Bone Mass ◽  
Proximal Tubule ◽  
Bone Remodeling ◽  
Kidney Function ◽  
Bone Cells ◽  
Critical Role ◽  
Renal Proximal Tubule ◽  
Proximal Tubule Cell ◽  
Protective Effects ◽  
Cannabinoid 1 Receptor

The renal proximal tubule cells (RPTCs), well-known for maintaining glucose and mineral homeostasis, play a critical role in the regulation of kidney function and bone remodeling. Deterioration in RPTC function may therefore lead to the development of diabetic kidney disease (DKD) and osteoporosis. Previously, we have shown that the cannabinoid-1 receptor (CB1R) modulates both kidney function as well as bone remodeling and mass via its direct role in RPTCs and bone cells, respectively. Here we employed genetic and pharmacological approaches that target CB1R, and found that its specific nullification in RPTCs preserves bone mass and remodeling both under normo- and hyper-glycemic conditions, and that its chronic blockade prevents the development of diabetes-induced bone loss. These protective effects of negatively targeting CB1R specifically in RPTCs were associated with its ability to modulate erythropoietin (EPO) synthesis, a hormone known to affect bone mass and remodeling. Our findings highlight a novel molecular mechanism by which CB1R in RPTCs remotely regulates skeletal homeostasis via a kidney-to-bone axis that involves EPO.

Structural, QSAR, machine learning and molecular docking studies of 5-thiophen-2-yl pyrazole derivatives as potent and selective cannabinoid-1 receptor antagonists

2021 ◽  
Author(s):  
Riad Hanachi ◽  
Ridha Ben Said ◽  
Hamza Allal ◽  
Seyfeddine Rahali ◽  
Mohammed A. M. Alkhalifah ◽  
...  
Keyword(s):  
Machine Learning ◽  
Biological Activity ◽  
Molecular Docking ◽  
Theoretical Analysis ◽  
Structural Study ◽  
Docking Studies ◽  
Pyrazole Derivatives ◽  
Molecular Docking Studies ◽  
Cannabinoid 1 Receptor ◽  
Chemical Descriptors

We performed a structural study followed by a theoretical analysis of the chemical descriptors and the biological activity of a series of 5-thiophen-2-yl pyrazole derivatives as potent and selective Cannabinoid-1...

scholarly journals Structural Features for Functional Selectivity at Serotonin Receptors

Science ◽  
2013 ◽  
Vol 340 (6132) ◽  
pp. 615-619 ◽  
Author(s):  
D. Wacker ◽  
C. Wang ◽  
V. Katritch ◽  
G. W. Han ◽  
X.-P. Huang ◽  
...  
Keyword(s):  
Serotonin Receptors ◽  
Structural Features ◽  
Functional Selectivity

Synthesis and evaluation of N-[(1S,2S)-3-(4-chlorophenyl)-2-(3-cyanophenyl)-1-methylpropyl]-2-methyl-2-aminopropanamide as human cannabinoid-1 receptor (CB1R) inverse agonists

2009 ◽  
Vol 19 (17) ◽  
pp. 5195-5199 ◽  
Author(s):  
Wu Du ◽  
James P. Jewell ◽  
Linus S. Lin ◽  
Vincent J. Colandrea ◽  
Jing C. Xiao ◽  
...  
Keyword(s):  
Inverse Agonists ◽  
Cannabinoid 1 Receptor

Protection of Intestinal Barrier in Uremic Mice by Electroacupuncture via Regulating the Cannabinoid 1 Receptor of the Intestinal Glial Cells

2021 ◽  
Vol 17 (11) ◽  
pp. 2210-2218
Author(s):  
Feng Li ◽  
Guangjian Zhang ◽  
Jing Liang ◽  
Yu Ma ◽  
Jian Huang ◽  
...  
Keyword(s):  
Tight Junction ◽  
Glial Cells ◽  
Cannabinoid Receptor ◽  
Intestinal Barrier ◽  
Mice Model ◽  
Jnk Pathway ◽  
Cannabinoid 1 Receptor ◽  
Junction Protein ◽  
Receptor Signaling Pathway ◽  
Junction Proteins

Intestinal barrier injuries are common in uremia, which aggravates uremia. The goal of this study is to learn moreabout how electroacupuncture regulates gastrointestinal function, as well as to identify the importance of microglia in electroacupuncture regulation and the cannabinoid receptor signaling pathway in controlling the activity of intestinal glial cells. The mice were arbitrarily assigned to four groups: control, CKD, electroacupuncture stimulation, or AM251 (CB1 receptor antagonist). The mice model of uremia was established by adenine gavage. Western blotting revealed the development of tight junction proteins ZO-1, cannabinoid 1 receptor, glial specific GFAP, occludin, S100 β, claudin-1, and JNK. GFAP and CB1R protein expression and co-localization of the intestinal glial cells were observed by double-labeled fluorescence. The expression of cannabinoid 1 receptor CB1R in the intestinal glial cells was increased after electroacupuncture. The expression of tight junction protein, GFAP, S100 β, and CB1R protein was up-regulated after electroacupuncture, and the dysfunction of the intestinal barrier in uremia was corrected. Nevertheless, AM251, a CB1R antagonist, reversed the effect of electroacupuncture. Electroacupuncture can protect the intestinal barrier through the intestinal glial cell CB1R, and the effect is achieved by inhibiting the JNK pathway.

Abstract 400: Cannabinoid 1 Receptor Blockade Diminishes Obesity and Dyslipidemia via Peripheral Activation of Brown Adipose Tissue

2014 ◽  
Vol 34 (suppl_1) ◽  
Author(s):  
Jimmy F Berbée ◽  
Mariëtte R Boon ◽  
Andrea D van Dam ◽  
Anita M van den Hoek ◽  
Marc Lombès ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Energy Expenditure ◽  
Brown Adipose Tissue ◽  
Therapeutic Potential ◽  
Lipoprotein Metabolism ◽  
Special Focus ◽  
Cannabinoid 1 Receptor ◽  
Brown Adipose ◽  
Major Player ◽  
Peripheral Activation

Objectives: The endocannabinoid system is an important player in energy metabolism by regulating appetite, lipolysis and energy expenditure. Chronic blockade of the cannabinoid 1 receptor (CB1R) leads to long-term maintained weight loss and reduction of dyslipidemia in experimental and human obesity. Brown adipose tissue (BAT) that burns lipids towards heat using UCP1, recently emerged as a major player in lipoprotein metabolism and is present and active in human adults. The aim of the present study was to elucidate the mechanism by which CB1R blockade reverses dyslipidemia and obesity, with special focus on BAT. Methods and results: Diet-induced obese APOE*3-Leiden.CETP transgenic mice, a well-established model for human-like lipoprotein metabolism, were treated with the systemic CB1R blocker rimonabant (10 mg/kg/day) for 4 weeks. Rimonabant persistently decreased body weight (-25%, p<0.001), fat mass (-32%, p<0.001) and plasma triglyceride (TG) levels (-60%, p<0.05), despite a modest and transient reduction in food intake. Interestingly, rimonabant reduced plasma TG levels, not by affecting VLDL-TG production by the liver, but rather by selectively increasing VLDL-TG clearance by BAT (+40%, p<0.05). This was accompanied by increased energy expenditure (+20%, p<0.05), decreased lipid droplet size and increased UCP1 content in BAT (+28%, p<0.05), all pointing to increased BAT activity. Next, we demonstrated that the CB1R is highly expressed in BAT and that in vitro blockade of the CB1R in cultured brown adipocytes resulted in 2.5-fold upregulation of UCP1. Importantly, the in vivo results could be fully recapitulated using the strictly peripheral CB1R antagonist AM6545 (10 mg/kg/day) that does not induce hypophagia. Conclusion: CB1R blockade reduces dyslipidemia and obesity by peripheral activation of BAT. Selective targeting of peripheral CB1R in BAT has thus great therapeutic potential in decreasing dyslipidemia and obesity and ultimately cardiovascular diseases.

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